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Wang P, Zhu P, Li ZY, Zhao YL, Mao FY, Peng LS, Luo SL, Luo P, Liu YG, Chen M, Zhuang Y. Expression, regulation, function and clinical significance of B7-H6 on neutrophils in human gastric cancer. Neoplasia 2025; 62:101149. [PMID: 40054066 PMCID: PMC11930213 DOI: 10.1016/j.neo.2025.101149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/18/2025]
Abstract
Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation, function and clinical relevance of neutrophils in human GC are presently unknown. We used flow cytometry analyses to examine levels and phenotype of neutrophils in samples from 50 patients with GC. Kaplan-Meier plots for patient survival were performed using the log-rank test, and multivariate analysis of prognostic factors for patient survival was performed using the Cox proportional hazards model. Neutrophils were isolated, stimulated and/or cultured for regulation and function assays. We found that GC patients showed a significantly higher neutrophil infiltration in tumors, and that neutrophil infiltration was positively associated with tumor progression but negatively correlated with patient survival. Most tumor-infiltrating neutrophils showed an activated CD54+ phenotype and expressed high level B7-H6. Tumor tissue culture supernatants from GC patients inhibited neutrophil apoptosis and induced the expression of CD54 and B7-H6 on neutrophils in time-dependent and dose-dependent manners. Intratumoral CD54+ neutrophils and B7-H6+ neutrophils positively correlated with increased G-CSF detection ex vivo; and in vitro both G-CSF and tumor-derived G-CSF induced the expression of CD54 and B7-H6 on neutrophils via NF-κB signaling pathway activation. Furthermore, blockade of B7-H6 promoted the apoptosis of tumor-infiltrating and tumor-conditioned neutrophils, and shortened their lifespan. Importantly, intratumoral B7-H6+ neutrophils increased with tumor progression and predicted poor patient survival. Our results illuminate a novel mechanism of B7-H6 expression on tumor-activated neutrophils in GC, and also suggest B7-H6+ neutrophils would be novel potential biomarkers in GC.
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Affiliation(s)
- Pan Wang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, The 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou, China
| | - Peng Zhu
- Department of Gastroenterology, Suining First People's Hospital, Suining, Sichuan, China
| | - Zheng-Yan Li
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Shou-Lu Luo
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ping Luo
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yu-Gang Liu
- Department of Laboratory Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China.
| | - Mao Chen
- Department of Neurology, XinQiao Hospital, Third Military Medical University, Chongqing, China.
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; Department of Endoscopy and Digestive System, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
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Gong Y, Luo Q, Tan H, Long J, Hu L, Al-Saadawe MAAH, Yao J, Lyu X, Qiu L, Wu G. Tumor-educated Neutrophils Induce Epithelial-mesenchymal Transition and Metastasis in Colorectal Cancer Through Interleukin-17a Secretion. Cytokine 2025; 190:156928. [PMID: 40156998 DOI: 10.1016/j.cyto.2025.156928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 01/19/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025]
Abstract
The role of neutrophils in defending against infections and regulating immune responses is well-known. In cancer, tumor-associated neutrophils also play a significant role in the progression of tumors. However, the specific mechanisms of their interaction with human colorectal tumors have not been fully elucidated. Our study found that tumor-educated neutrophils can activate the STAT3 signaling pathway in colorectal cancer cells by secreting IL-17a. This leads to increased migration and invasion of colorectal cancer cells, promoting tumor growth by triggering epithelial-to-mesenchymal transition (EMT). These findings suggest that IL-17a secreted by tumor-educated neutrophils contributes to the development of colorectal cancer through the IL-17a/STAT3 signaling pathway. This provides new insights for potential treatments for colorectal cancer.
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Affiliation(s)
- Yibing Gong
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Qingshuang Luo
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Haiqi Tan
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Longtai Hu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Moyed Abd Alhussain Hamza Al-Saadawe
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Jinke Yao
- Department of general surgery, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511300, China
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University. Guangzhou, Guangdong 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China.
| | - Lizhen Qiu
- Health Management Center, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511300, China.
| | - Gongfa Wu
- Department of pathology, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511300, China.
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Zhang X, Li B, Lan T, Chiari C, Ye X, Wang K, Chen J. The role of interleukin-17 in inflammation-related cancers. Front Immunol 2025; 15:1479505. [PMID: 39906741 PMCID: PMC11790576 DOI: 10.3389/fimmu.2024.1479505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/27/2024] [Indexed: 02/06/2025] Open
Abstract
Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity in several models of grafted subcutaneous tumors. Additionally, dynamic changes in the microbiome can influence the secretion of IL-17, thereby affecting tumor development. The specific role of IL-17 is contingent upon its functional classification, spatiotemporal characteristics, and the stage of tumor development. In this review, we introduce the fundamental biology of IL-17 and the expression profile of its receptors in cancer, while also reviewing and discussing recent advancements regarding the pleiotropic effects and mechanisms of IL-17 in inflammation-related cancers. Furthermore, we supplement our discussion with insights into the mechanisms by which IL-17 impacts cancer progression through interactions with the microbiota, and we explore the implications of IL-17 in cancer therapy. This comprehensive analysis aims to enhance our understanding of IL-17 and its potential role in cancer treatment.
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Affiliation(s)
- Xingru Zhang
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Bangjie Li
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
| | - Tian Lan
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Conner Chiari
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Xiaoyang Ye
- College of Engineering, Northeastern University, Seattle, WA, United States
| | - Kepeng Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Ju Chen
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
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Li J, Liu Q, Duan W, Duan Z, Liu F, Ruan M, Zong Q, Zhang H, Zhou Q, Wang Q. Intrahepatic CD161 hiCD8+T Cell Recruitment Has a Pathogenetic Potential in Chronic HBV Infection. Immun Inflamm Dis 2025; 13:e70118. [PMID: 39799583 PMCID: PMC11725298 DOI: 10.1002/iid3.70118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 10/22/2024] [Accepted: 12/20/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUNDS AND AIMS CD8+T cells are crucially associated with the fight against hepatitis B virus (HBV) infection. CD161 has been shown to express remarkably on HCV-specific CD8+T cells. However, the accurate function of CD161+CD8+T cells in HBV immunity or pathogenesis remains undetermined. METHODS Blood samples were collected from 25 chronic hepatitis B (CHB) patients. Peripheral blood levels of CD161+CD8+T cells and their correlation with serum ALT levels were analyzed in CHB patients. To analyze the in vivo CD161+CD8+T cell's number, function, and intrahepatic recruitment characteristics, HBV replication mouse models were established. The expression of CD161 on HBV-specific CD8+T cells was also detected by analyzing CD161+CD8+T cell functions during infection. RESULTS Patients with CHB infection had a markedly lower peripheral blood frequency of CD161+CD8+T cells than did healthy controls and negatively correlated with serum ALT level. Furthermore, compared to the control mice, the frequency of CD161+CD8+T cells was significantly decreased in the blood of acute and chronic HBV-replicating mice. Moreover, CHB-replicating mice had significantly increased hepatic levels of CD161+CD8+T cells, which was not observed in the acute group of mice. Additionally, the CD161+CD8+T cells were categorized into CD161hi and CD161intCD8+T cells and it was revealed that in the liver of CHB-replicating mice the primary recruited cells were CD161hiCD8+T. Intrahepatic CD161hiCD8+T cells demonstrated increased CXCR6 expression, enhanced production of cytokine IL-17 and TNF-ɑ, and reduced IFN-γ secretion. Accordingly, the CXCL16 mRNA expression in the liver tissue of CHB-replication mice was markedly higher than in acute HBV-replicating and control mice. The study also revealed that HBV-specific CD8+T cells were mainly CD161-CD8+T cells. CONCLUSION During HBV infection, the intrahepatic recruitment of CD161+CD8+T cells was mainly CD161hiCD8+T cell subpopulation, which has a weak antiviral response, but increased pro-inflammatory effect, suggesting that CD161 may serve as a potential marker of liver-damaging T cells.
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Affiliation(s)
- Jianfei Li
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qian Liu
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanlu Duan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi Duan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Futing Liu
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mengqi Ruan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiyin Zong
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Zhang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiang Zhou
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qin Wang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
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Li W, Huang X, Han X, Zhang J, Gao L, Chen H. IL-17A in gastric carcinogenesis: good or bad? Front Immunol 2024; 15:1501293. [PMID: 39676857 PMCID: PMC11638189 DOI: 10.3389/fimmu.2024.1501293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/13/2024] [Indexed: 12/17/2024] Open
Abstract
Cytokines, which are important to the tumor microenvironment (TME), play critical roles in tumor development, metastasis, and immune responses. Interleukin-17(IL-17) has emerged as a key biomarker in many malignancies; however, its precise involvement in gastric cancer is less fully understood. Elevated levels of IL-17 have been observed in stomach diseases such as Helicobacter pylori infection and autoimmune gastritis, indicating that a sustained Th17 response may precede the development of gastric cancer. While IL-17 is related to inflammatory processes that may lead to cancer, its specific influence on gastric cancer development and therapy needs to be completely understood. Specifically, the release of IL-17A by diverse immune cells has been associated with both tumor development and inhibition in gastric cancer. It may impact tumor development through mechanisms such as boosting cell proliferation, inducing angiogenesis, and enabling immune cell recruitment or, conversely, suppressing tumor growth via the activation of anti-tumor immune responses. The dual role of IL-17 in cancer, along with its various effects depending on the TME and immune cell composition, highlights the complexity of its activity. Current research reveals that although IL-17 might serve as a target for immunotherapy, its therapeutic potential is hindered by its various activities. Some studies have shown that anti-IL-17 drugs may be helpful, especially when paired with immune checkpoint inhibitors, whereas others point to concerns about the validity of IL-17 in gastric cancer therapy. The lack of clinical trials and the heterogeneity of human tumors underscore the necessity for individualized treatment approaches. Further studies are needed to identify the specific mechanisms of IL-17 in gastric cancer and to design targeted therapeutics appropriately.
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Affiliation(s)
- Weidong Li
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Xiaodong Huang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Xiaowen Han
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Jiayi Zhang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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Xu J, Yu B, Wang F, Yang J. Single-cell RNA sequencing to map tumor heterogeneity in gastric carcinogenesis paving roads to individualized therapy. Cancer Immunol Immunother 2024; 73:233. [PMID: 39271545 PMCID: PMC11399521 DOI: 10.1007/s00262-024-03820-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024]
Abstract
Gastric cancer (GC) is a highly heterogeneous disease with a complex tumor microenvironment (TME) that encompasses multiple cell types including cancer cells, immune cells, stromal cells, and so on. Cancer-associated cells could remodel the TME and influence the progression of GC and therapeutic response. Single-cell RNA sequencing (scRNA-seq), as an emerging technology, has provided unprecedented insights into the complicated biological composition and characteristics of TME at the molecular, cellular, and immunological resolutions, offering a new idea for GC studies. In this review, we discuss the novel findings from scRNA-seq datasets revealing the origin and evolution of GC, and scRNA-seq is a powerful tool for investigating transcriptional dynamics and intratumor heterogeneity (ITH) in GC. Meanwhile, we demonstrate that the vital immune cells within TME, including T cells, B cells, macrophages, and stromal cells, play an important role in the disease progression. Additionally, we also overview that how scRNA-seq facilitates our understanding about the effects on individualized therapy of GC patients. Spatial transcriptomes (ST) have been designed to determine spatial distribution and capture local intercellular communication networks, enabling a further understanding of the relationship between the spatial background of a particular cell and its functions. In summary, scRNA-seq and other single-cell technologies provide a valuable perspective for molecular and pathological disease characteristics and hold promise for advancing basic research and clinical practice in GC.
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Affiliation(s)
- Jiao Xu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Bixin Yu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Fan Wang
- Phase I Clinical Trial Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
| | - Jin Yang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road., Xi'an, 710061, Shaanxi, People's Republic of China.
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road., Xi'an, 710061, Shaanxi, People's Republic of China.
- Phase I Clinical Trial Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
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Zhang Y, Li J, Li J, Wang J. Dysregulation of systemic immunity and its clinical application in gastric cancer. Front Immunol 2024; 15:1450128. [PMID: 39301031 PMCID: PMC11410619 DOI: 10.3389/fimmu.2024.1450128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/22/2024] [Indexed: 09/22/2024] Open
Abstract
Immunotherapy has profoundly changed the treatment of gastric cancer, but only a minority of patients benefit from immunotherapy. Therefore, numerous studies have been devoted to clarifying the mechanisms underlying resistance to immunotherapy or developing biomarkers for patient stratification. However, previous studies have focused mainly on the tumor microenvironment. Systemic immune perturbations have long been observed in patients with gastric cancer, and the involvement of the peripheral immune system in effective anticancer responses has attracted much attention in recent years. Therefore, understanding the distinct types of systemic immune organization in gastric cancer will aid personalized treatment designed to pair with traditional therapies to alleviate their detrimental effects on systemic immunity or to directly activate the anticancer response of systemic immunity. Herein, this review aims to comprehensively summarize systemic immunity in gastric cancer, including perturbations in systemic immunity induced by cancer and traditional therapies, and the potential clinical applications of systemic immunity in the detection, prediction, prognosis and therapy of gastric cancer.
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Affiliation(s)
- Yao Zhang
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Junfeng Li
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jisheng Wang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
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Shirani M, Shariati S, Bazdar M, Sojoudi Ghamnak F, Moradi M, Shams Khozani R, Taki E, Arabsorkhi Z, Heidary M, Eskandari DB. The immunopathogenesis of Helicobacter pylori-induced gastric cancer: a narrative review. Front Microbiol 2024; 15:1395403. [PMID: 39035439 PMCID: PMC11258019 DOI: 10.3389/fmicb.2024.1395403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/06/2024] [Indexed: 07/23/2024] Open
Abstract
Helicobacter pylori infection is a well-established risk factor for the development of gastric cancer (GC). Understanding the immunopathogenesis underlying this association is crucial for developing effective preventive and therapeutic strategies. This narrative review comprehensively explores the immunopathogenesis of H. pylori-induced GC by delving into several key aspects, emphasizing the pivotal roles played by H. pylori virulence factors, including cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA), blood group antigen-binding adhesin (babA), and sialic acid binding adhesin (sabA). Moreover, the review focuses on the role of toll-like receptors (TLRs) and cytokines in the complex interplay between chronic infection and gastric carcinogenesis. Finally, the study examines the association between H. pylori evasion of the innate and adaptive immune response and development of GC. A comprehensive understanding of the immunopathogenesis of H. pylori-induced GC is essential for designing targeted interventions to prevent and manage this disease. Further research is warranted to elucidate the intricate immune responses involved and identify potential therapeutic targets to improve patient outcomes.
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Affiliation(s)
- Maryam Shirani
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeedeh Shariati
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Monireh Bazdar
- School of Medicine, Razi Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Melika Moradi
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Elahe Taki
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Arabsorkhi
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohsen Heidary
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran
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Koh CH, Kim BS, Kang CY, Chung Y, Seo H. IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials. Immune Netw 2024; 24:e2. [PMID: 38455465 PMCID: PMC10917578 DOI: 10.4110/in.2024.24.e2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/26/2023] [Accepted: 01/07/2024] [Indexed: 03/09/2024] Open
Abstract
Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Korea
| | - Chang-Yuil Kang
- Research & Development Center, Cellid Co., Ltd., Seoul 08826, Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Hyungseok Seo
- Laboratory of Cell & Gene Therapy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
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10
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Ren C, Wang Q, Xu Z, Pan Y, Wang S, Liu X. Upregulation of CCNB2 and a novel lncRNAs-related risk model predict prognosis in clear cell renal cell carcinoma. J Cancer Res Clin Oncol 2024; 150:64. [PMID: 38300330 PMCID: PMC10834599 DOI: 10.1007/s00432-024-05611-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 01/04/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the main type of renal cell carcinoma. Cyclin B2 (CCNB2) is a subtype of B-type cyclin that is associated with the prognosis of several cancers. This study aimed to identify the relationship between CCNB2 and progression of ccRCC and construct a novel lncRNAs-related model to predict prognosis of ccRCC patients. METHODS The data were obtained from public databases. We identified CCNB2 in ccRCC using Kaplan-Meier survival analysis, univariate and multivariate Cox regression, and Gene Ontology analysis. External validation was then performed. The risk model was constructed based on prognostic lncRNAs by the LASSO algorithm and multivariate Cox regression. Receiver operating characteristics (ROC) curves were used to evaluate the model. Consensus clustering analysis was performed to re-stratify the patients. Finally, we analyzed the tumor-immune microenvironment and performed screening of potential drugs. RESULTS CCNB2 associated with late clinicopathological parameters and poor prognosis in ccRCC and was an independent predictor for disease-free survival. In addition, CCNB2 shared the same expression pattern with known suppressive immune checkpoints. A risk model dependent on the expression of three prognostic CCNB2-related lncRNAs (SNHG17, VPS9D1-AS1, and ZMIZ1-AS1) was constructed. The risk signature was an independent predictor of ccRCC. The area under the ROC (AUC) curve for overall survival at 1-, 3-, 5-, and 8-year was 0.704, 0.702, 0.741, and 0.763. The high-risk group and cluster 2 had stronger immunogenicity and were more sensitive to immunotherapy. CONCLUSION CCNB2 could be an important biomarker for predicting prognosis in ccRCC patients. Furthermore, we developed a novel lncRNAs-related risk model and identified two CCNB2-related molecular clusters. The risk model performed well in predicting overall survival and immunological microenvironment of ccRCC.
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Affiliation(s)
- Congzhe Ren
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China
| | - Qihua Wang
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China
| | - Zhunan Xu
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China
| | - Yang Pan
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China
| | - Shangren Wang
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China
| | - Xiaoqiang Liu
- Department of Urology, Tianjin Medical University General Hospital, Heping District, 154 Anshan Road, Tianjin, 300052, China.
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Chen J, Madina BR, Ahmadi E, Yarovinsky TO, Krady MM, Meehan EV, Wang IC, Ye X, Pitmon E, Ma XY, Almassian B, Nakaar V, Wang K. Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence. Acta Pharm Sin B 2024; 14:335-349. [PMID: 38261838 PMCID: PMC10792965 DOI: 10.1016/j.apsb.2023.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/01/2023] [Accepted: 08/15/2023] [Indexed: 01/25/2024] Open
Abstract
Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
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Affiliation(s)
- Ju Chen
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan 528000, China
| | | | - Elham Ahmadi
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
- CaroGen Corporation, Farmington, CT 06030, USA
| | | | | | - Eileen Victoria Meehan
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Isabella China Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
- The Loomis Chaffee School, Windsor, CT 06095, USA
| | - Xiaoyang Ye
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Elise Pitmon
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
| | | | | | | | - Kepeng Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
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12
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Khan IA, Singh N, Gunjan D, Dash NR, Nayak B, Gupta S, Saraya A. Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma. Hum Immunol 2024; 85:110748. [PMID: 38177009 DOI: 10.1016/j.humimm.2023.110748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/12/2023] [Accepted: 12/29/2023] [Indexed: 01/06/2024]
Abstract
AIM Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.
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Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India.
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13
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Bachari A, Nassar N, Schanknecht E, Telukutla S, Piva TJ, Mantri N. Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment. WIREs Mech Dis 2024; 16:e1633. [PMID: 37920964 DOI: 10.1002/wsbm.1633] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/21/2023] [Accepted: 10/06/2023] [Indexed: 11/04/2023]
Abstract
Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor. This article is categorized under: Cancer > Molecular and Cellular Physiology.
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Affiliation(s)
- Ava Bachari
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, Victoria, Australia
| | - Nazim Nassar
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Ellen Schanknecht
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, Victoria, Australia
| | | | - Terrence Jerald Piva
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Nitin Mantri
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, Victoria, Australia
- The UWA Institute of Agriculture, The University of Western Australia, Perth, Western Australia, Australia
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14
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Liu K, Yuan S, Wang C, Zhu H. Resistance to immune checkpoint inhibitors in gastric cancer. Front Pharmacol 2023; 14:1285343. [PMID: 38026944 PMCID: PMC10679741 DOI: 10.3389/fphar.2023.1285343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. In the past decade, with the development of early diagnostic techniques, a clear decline in GC incidence has been observed, but its mortality remains high. The emergence of new immunotherapies such as immune checkpoint inhibitors (ICIs) has changed the treatment of GC patients to some extent. However, only a small number of patients with advanced GC have a durable response to ICI treatment, and the efficacy of ICIs is very limited. Existing studies have shown that the failure of immunotherapy is mainly related to the development of ICI resistance in patients, but the understanding of the resistance mechanism is still insufficient. Therefore, clarifying the mechanism of GC immune resistance is critical to improve its treatment and clinical benefit. In this review, we focus on summarizing the mechanisms of primary or acquired resistance to ICI immunotherapy in GC from both internal and external aspects of the tumor. At the same time, we also briefly discuss some other possible resistance mechanisms in light of current studies.
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Affiliation(s)
- Kai Liu
- The Clinical Medical College, Guizhou Medical University, Guiyang, China
| | - Shiman Yuan
- The Clinical Medical College, Guizhou Medical University, Guiyang, China
| | - Chenyu Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Hong Zhu
- Cancer Center, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China
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15
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Wang J, Peng Z, Guo J, Wang Y, Wang S, Jiang H, Wang M, Xie Y, Li X, Hu M, Xie Y, Cheng H, Li T, Jia L, Song J, Wang Y, Hou J, Liu Z. CXCL10 Recruitment of γδ T Cells into the Hypoxic Bone Marrow Environment Leads to IL17 Expression and Multiple Myeloma Progression. Cancer Immunol Res 2023; 11:1384-1399. [PMID: 37586075 DOI: 10.1158/2326-6066.cir-23-0088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/16/2023] [Accepted: 08/15/2023] [Indexed: 08/18/2023]
Abstract
In multiple myeloma (MM), bone marrow stromal cells (BMSC) shape a unique niche within the bone marrow, promoting T-cell dysfunction and driving MM progression; however, the precise underlying mechanisms remain elusive. Here, we show that BMSC-mediated reprogramming of MM cells led to heightened production of CXCL10. CXCL10 orchestrated the recruitment of γδ T cells into the bone marrow, and this was observed in both the Vk*MYC and 5TGM1 mouse models of MM, as well as in patients experiencing refractory or relapsed MM. Furthermore, the dysfunctional γδ T cells in the MM bone marrow niche exhibited increased PD-1 expression and IL17 production. In the Vk*MYC mouse model, MM-associated bone lesions and mortality were markedly alleviated in Tcrd-/- mice, and MM disease progression could be rescued in these mice upon transplantation of γδ T cells expanded from wild-type mice, but not from Il17-/- mice. Mechanistically, the hypoxic microenvironment prevailing in the MM bone marrow niche stimulated the expression of steroid receptor coactivator 3 (SRC-3) in γδ T cells, which in turn interacted with the transcriptional factor RORγt, promoting Il17 transcription. Pharmacologic inhibition of SRC-3 utilizing SI-2 effectively suppressed Il17A expression in γδ T cells, leading to alleviation of MM progression in the murine models and enhancing the anti-multiple myeloma efficacy of bortezomib. Our results illuminated the bone marrow microenvironment's involvement in provoking γδ T-cell dysfunction throughout MM progression and suggest SRC-3 inhibition as a promising strategy to enhance the effectiveness of immunotherapies targeting γδ T cells.
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Affiliation(s)
- Jingya Wang
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Ziyi Peng
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Jing Guo
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Yixuan Wang
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Sheng Wang
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Hongmei Jiang
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Mengqi Wang
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Ying Xie
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Xin Li
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Meilin Hu
- Tianjin Medical University School of Stomatology, Heping, Tianjin, China
| | - Yangyang Xie
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Hao Cheng
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Tiantian Li
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Linchuang Jia
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
| | - Jia Song
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yafei Wang
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jian Hou
- Department of Hematology, Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiqiang Liu
- State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China
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16
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Khan IA, Singh N, Gunjan D, Gopi S, Dash NR, Gupta S, Saraya A. Increased circulating Th17 cell populations in patients with pancreatic ductal adenocarcinoma. Immunogenetics 2023; 75:433-443. [PMID: 37540314 DOI: 10.1007/s00251-023-01318-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/27/2023] [Indexed: 08/05/2023]
Abstract
T-helper 17 (Th17) cells are a subset of CD4+ helper T cells that produce interleukin 17 (IL-17) and play a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Few studies have been conducted to determine the role of Th17 cells in the tumorigenesis and development of pancreatic ductal adenocarcinoma (PDAC); however, its role is still unclear. In this study, the percentage of circulating Th17 cells and serum levels of IL-17A and IL-23 were analyzed using flow cytometry and ELISA, respectively, in 40 PDAC patients, 30 chronic pancreatitis (CP) patients and 30 healthy controls (HC). In addition, the mRNA expression levels of IL-17A, STAT3 and RORγt in tissue samples were quantified by qRT-PCR. The results showed that the percentage of circulating Th17 cells and the concentrations of serum IL-17A and IL-23 were significantly increased in PDAC patients as compared to CP and HC (P < 0.001). In addition, the higher level of IL-17A was significantly correlated with the poor overall survival of the PDAC patients. Furthermore, the frequencies of Th17 cells and IL-17A were significantly higher in stage III+IV PDAC patients versus stage I+II. A significant increase in IL-17A, STAT3 and RORγT mRNA was observed in patients with PDAC. Taken together, these findings suggest that the increased circulating Th17 cells and serum IL-17A may be involved in the development and metastasis of PDAC, and thus represent potential targets for the treatment of PDAC.
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Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, 110029, Ansari Nagar, New Delhi, India
| | - Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, 110029, Ansari Nagar, New Delhi, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, 110029, Ansari Nagar, New Delhi, India
| | - Srikant Gopi
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, 110029, Ansari Nagar, New Delhi, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, 110029, Ansari Nagar, New Delhi, India.
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17
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Nakashima K, Haruki K, Kamada T, Takahashi J, Nakaseko Y, Ohdaira H, Furukawa K, Suzuki Y, Ikegami T. Usefulness of the cachexia index as a prognostic indicator for patients with gastric cancer. Ann Gastroenterol Surg 2023; 7:733-740. [PMID: 37663966 PMCID: PMC10472360 DOI: 10.1002/ags3.12669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 09/05/2023] Open
Abstract
Aim Cachexia is associated with the morbidity and mortality of cancer patients. The cachexia index (CXI) is a novel biomarker of cachexia associated with the prognosis for certain cancers. This study analyzed the relationship between CXI with long-term outcomes of gastric cancer patients. Methods We included 175 gastric cancer patients who underwent curative gastrectomy at our hospital between January 2011 and October 2019. The CXI was calculated using skeletal muscle index, serum albumin level, and neutrophil-to-lymphocyte ratio. The prognostic value of CXI was investigated by univariate and multivariate Cox hazard regression models adjusting for potential confounders. Results In the multivariate analyses, tumor location (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11-0.49; p < 0.01), disease stage (HR, 15.4; 95% CI, 4.18-56.1; p < 0.01), and low CXI (HR, 2.97; 95% CI, 1.01-8.15; p = 0.03) were independent and significant predictors of disease-free survival. Disease stage (HR, 9.88; 95% CI, 3.53-29.1; p < 0.01) and low CXI (HR, 4.07; 95% CI, 1.35-12.3; p < 0.01) were independent and significant predictors of overall survival. The low CXI group had a lower body mass index (p = 0.02), advanced disease stage (p = 0.034), and a lower prognostic nutritional index (p < 0.01). Conclusions Cachexia index is associated with a poor prognosis for gastric cancer, suggesting the utility of comprehensive assessment using nutritional, physical, and inflammatory status.
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Affiliation(s)
- Keigo Nakashima
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Teppei Kamada
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Junji Takahashi
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Yuichi Nakaseko
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Hironori Ohdaira
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Yutaka Suzuki
- Department of SurgeryInternational University of Health and Welfare HospitalTochigiJapan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe Jikei University School of MedicineTokyoJapan
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18
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Zhang Z, Liu S, Gao T, Yang Y, Li Q, Zhao L. A novel immune-related prognostic signature based on Chemoradiotherapy sensitivity predicts long-term survival in patients with esophageal squamous cell carcinoma. PeerJ 2023; 11:e15839. [PMID: 37609436 PMCID: PMC10441524 DOI: 10.7717/peerj.15839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/12/2023] [Indexed: 08/24/2023] Open
Abstract
Background There is a heterogenous clinical response following chemoradiotherapy (CRT) in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to study signaling pathway genes that affect CRT sensitivity and prognosis. Methods Gene expression analyses were performed in the GEO and TCGA datasets. A immunohistochemistry (IHC) analysis was performed in pretreatment biopsies. Results MMP13 was found to be highly expressed in the "Pathologic Complete Response (pCR)" and "Complete Remission (CR)" and "Alive" groups. Th17 cells and MMP9/13 showed a negative correlation in immune infiltration analysis. In GSEA analysis, IL-4 and IL-13 signaling pathways were highly enriched in patients exhibiting high MMP expression in pCR and CR groups. IHC results suggested higher MMP13 & IL-4 and lower IL-17A & RORC expression in the CR group compared to the 0.70, and the model could well distinguish high-risk and low-risk subgroups. Conclusion The above results may provide guidance for developing novel treatment and prognostic strategies in ESCC patients.
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Affiliation(s)
- Zewei Zhang
- Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Shiliang Liu
- Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Tiantian Gao
- Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Yuxian Yang
- Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Quanfu Li
- Ordos Central Hospital, Ordos, China
| | - Lei Zhao
- Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
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19
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Picard FSR, Lutz V, Brichkina A, Neuhaus F, Ruckenbrod T, Hupfer A, Raifer H, Klein M, Bopp T, Pfefferle PI, Savai R, Prinz I, Waisman A, Moos S, Chang HD, Heinrich S, Bartsch DK, Buchholz M, Singh S, Tu M, Klein L, Bauer C, Liefke R, Burchert A, Chung HR, Mayer P, Gress TM, Lauth M, Gaida M, Huber M. IL-17A-producing CD8 + T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts. Gut 2023; 72:1510-1522. [PMID: 36759154 PMCID: PMC10359545 DOI: 10.1136/gutjnl-2022-327855] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 01/21/2023] [Indexed: 02/11/2023]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. DESIGN Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. RESULTS Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. CONCLUSIONS We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.
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Affiliation(s)
| | - Veronika Lutz
- Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany
| | - Anna Brichkina
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Felix Neuhaus
- Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany
| | - Teresa Ruckenbrod
- Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany
| | - Anna Hupfer
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Hartmann Raifer
- Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany
- Core-Facility Flow Cytometry, Philipps-University Marburg, Marburg, Germany
| | - Matthias Klein
- Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Tobias Bopp
- Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Petra Ina Pfefferle
- Comprehensive Biomaterial Bank Marburg (CBBMR), Philipps-Universitat Marburg, Marburg, Germany
| | - Rajkumar Savai
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig Universitat, Giessen, Germany
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Immo Prinz
- Institute of Systems Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Sonja Moos
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Hyun-Dong Chang
- Institute of Biotechnology, Technische Universität, Berlin, Germany
- German Rheumatism Research Center (DRFZ), An Institute of the Leibniz Association, Berlin, Germany
| | - Stefan Heinrich
- Department of Surgery, Johannes Gutenberg University, Mainz, Germany
| | - Detlef K Bartsch
- Division of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - Malte Buchholz
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Shiv Singh
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Mengyu Tu
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Lukas Klein
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany
| | - Christian Bauer
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Robert Liefke
- Institute of Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
| | - Andreas Burchert
- Department of Hematology, Oncology and Immunology, Philipps University Marburg Faculty of Medicine, Marburg, Germany
| | - Ho-Ryun Chung
- Institute for Medical Bioinformatics and Biostatistics, Philipps-University Marburg, Marburg, Germany
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, Heidelberg University, Heidelberg, Germany
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Matthias Lauth
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Matthias Gaida
- Institute of Pathology, JGU Mainz, Mainz, Germany
- Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
- Joint Unit Immunopathology, Institute of Pathology, University Medical Center, JGU-Mainz and TRON, Translational Oncology at the University Medical Center, JGU-Mainz, Mainz, Germany
| | - Magdalena Huber
- Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany
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20
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Hipp AV, Bengsch B, Globig AM. Friend or Foe - Tc17 cell generation and current evidence for their importance in human disease. DISCOVERY IMMUNOLOGY 2023; 2:kyad010. [PMID: 38567057 PMCID: PMC10917240 DOI: 10.1093/discim/kyad010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/12/2023] [Accepted: 07/19/2023] [Indexed: 04/04/2024]
Abstract
The term Tc17 cells refers to interleukin 17 (IL-17)-producing CD8+ T cells. While IL-17 is an important mediator of mucosal defense, it is also centrally involved in driving the inflammatory response in immune-mediated diseases, such as psoriasis, multiple sclerosis, and inflammatory bowel disease. In this review, we aim to gather the current knowledge on the phenotypic and transcriptional profile, the in vitro and in vivo generation of Tc17 cells, and the evidence pointing towards a relevant role of Tc17 cells in human diseases such as infectious diseases, cancer, and immune-mediated diseases.
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Affiliation(s)
- Anna Veronika Hipp
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Bertram Bengsch
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Anna-Maria Globig
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
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21
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Deng S, Zhu Q, Chen H, Xiao T, Zhu Y, Gao J, Li Q, Gao Y. Screening of prognosis-related Immune cells and prognostic predictors in Colorectal Cancer Patients. BMC Cancer 2023; 23:195. [PMID: 36859111 PMCID: PMC9976376 DOI: 10.1186/s12885-023-10667-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
OBJECTIVE To accurately screen potential immune cells that can predict the survival of colorectal cancer (CRC) patients and identify related prognostic predictors. METHODS The sample data of CRC patients were downloaded from the GEO database as a training set to establish a prognosis-scoring model and screen prognosis-related immune cells. The sample data of CRC patients from the TCGA database were used as the validation set. Simultaneously, cancer tissue samples from 116 patients with CRC diagnosed pathologically in Shanghai Dongfang Hospital were collected to analyze the relationship of prognosis-related immune cells with patients' survival, and clinical and pathological parameters, and to screen prognostic predictors. RESULTS Prognosis-related immune cells screened from GEO and TCGA databases mainly included Follicular Helper T cells (Tfh), Monocytes and M2 Macrophages. In the training set, the 2,000- and 4,000-day survival rates were 48.3% and 10.7% in the low-risk group (N = 234), and 42.1% and 7.5% in the high-risk group (N = 214), respectively. In the validation set, the 2,000- and 4,000-day survival rates were 34.8% and 8.6% in the low-risk group (N = 187), and 28.9% and 6.1% in the high-risk group (N = 246), respectively. The prognosis of patients in the high-risk group was worse than that in the low-risk group (P < 0.05). Furthermore, the screened primary prognostic predictors were CD163 and CD4 + CXCR5. CD163 protein expression was distributed in Monocytes and M2 Macrophages. The 1,000- and 2,000-day survival rates were 56.1% and 7.0% in the CD163 low-expression group, and 40.7% and 1.7% in the high-expression group (N = 214), respectively, showing a worse prognosis in the high-expression group than that in the low-expression group. Meanwhile, the immune marker CD4 + CXCR5 could identify Tfh. The 1,000- and 2,000-day survival rates were 63.9% and 5.6% in the CD4 + CXCR5 high-expression group, and 33.3% and 2.8% in the low-expression group (N = 214), respectively, with a better prognosis in the high-expression group than that in the low-expression group. CONCLUSION Prognostic-related immune cells of CRC mainly include Tfh cells, Monocytes and M2 Macrophages. Monocytes and M2 Macrophages correlate negatively, while Tfh cells correlate positively with the prognosis of CRC patients. Immune markers CD163 and CD4 + CXCR5 can be considered as the prognostic predictors of CRC with clinical value of the application.
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Affiliation(s)
- Shuangshuang Deng
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qiping Zhu
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Hongyan Chen
- Department of Neurology, Luodian Hospital, Baoshan District, Shanghai, 201908, China
| | - Tianyu Xiao
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yinshen Zhu
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jinli Gao
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qing Li
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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22
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Lee YH, Chuah S, Nguyen PHD, Lim CJ, Lai HLH, Wasser M, Chua C, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Bonney GK, Chan CY, Chung A, Goh BKP, Zhai W, Chow PKH, Albani S, Liu H, Chew V. IFNγ -IL-17 + CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma. Cancer Lett 2023; 552:215977. [PMID: 36279983 DOI: 10.1016/j.canlet.2022.215977] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/12/2022] [Accepted: 10/18/2022] [Indexed: 11/07/2022]
Abstract
IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression.
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Affiliation(s)
- Yun Hua Lee
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Samuel Chuah
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Phuong H D Nguyen
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Chun Jye Lim
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Hannah L H Lai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Martin Wasser
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Camillus Chua
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Tony K H Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Wei Qiang Leow
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Tracy Jiezhen Loh
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Wei Keat Wan
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Yin Huei Pang
- Department of Pathology, National University Hospital Singapore, 119074, Singapore
| | - Gwyneth Soon
- Department of Pathology, National University Hospital Singapore, 119074, Singapore
| | - Peng Chung Cheow
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Juinn Huar Kam
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Shridhar Iyer
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore, 119074, Singapore
| | - Alfred Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore, 119074, Singapore
| | - Glenn K Bonney
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore, 119074, Singapore
| | - Chung Yip Chan
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Alexander Chung
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Weiwei Zhai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100107, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunan, 650223, China
| | - Pierce K H Chow
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, 169608, Singapore
| | - Salvatore Albani
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute, Immunology Translational Research Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, 169856, Singapore.
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23
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Arra A, Lingel H, Pierau M, Brunner-Weinzierl MC. PD-1 limits differentiation and plasticity of Tc17 cells. Front Immunol 2023; 14:1104730. [PMID: 37205114 PMCID: PMC10186197 DOI: 10.3389/fimmu.2023.1104730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/05/2023] [Indexed: 05/21/2023] Open
Abstract
Blockade of surface co-inhibitory receptor programmed cell death-1 (PD-1; CD279) has been established as an important immunotherapeutic approach to treat malignancies. On a cellular level, PD-1 is demonstrated to be of particular importance in inhibiting differentiation and effector function of cytotoxic Tc1 cells (CTLs). Nevertheless, the role of PD-1 in modulating interleukin (IL)-17-producing CD8+ T-cells (Tc17 cells), which generally display suppressed cytotoxic nature, is not well understood. To evaluate the impact of PD-1 in Tc17 responses, we examined its functioning using different in vitro and in vivo models. Upon activation of CD8+ T-cells in Tc17 environment, we found that PD-1 was rapidly expressed on the surface of CD8+ T-cells and triggered a T-cell-internal mechanism that inhibited the expression of IL-17 and Tc17-supporting transcription factors pSTAT3 and RORγt. Expression of type17-polarising cytokine IL-21 and the receptor for IL-23 were also suppressed. Intriguingly, adoptively transferred, PD-1-/- Tc17 cells were highly efficient in rejection of established B16 melanoma in vivo and displayed Tc1 like characteristics ex vivo. When using IL-17A-eGFP reporter mice for in vitro fate tracking, IL-17A-eGFP expressing cells lacking PD-1 signaling upon re-stimulation with IL-12 quickly acquired Tc1 characteristics such as IFN-γ, and granzyme B expression, implicating lineage independent upregulation of CTL-characteristics that are needed for tumor control. In line with plasticity characteristics, absence of PD-1 signaling in Tc17 cells increased the expression of the stemness and persistence-associated molecules TCF1 and BCL6. Thus, PD-1 plays a central role in the specific suppression of Tc17 differentiation and its plasticity in relation to CTL-driven tumor rejection, which provides further explanation as to why the blockade of PD-1 is such an efficient therapeutic target for inducing tumor rejection.
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Affiliation(s)
- Aditya Arra
- Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
| | - Holger Lingel
- Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
| | - Mandy Pierau
- Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
| | - Monika C. Brunner-Weinzierl
- Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
- *Correspondence: Monika C. Brunner-Weinzierl,
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24
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Li J, Qiu J, Han J, Li X, Jiang Y. Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic Pathway Signatures. Genes (Basel) 2022; 13:1976. [PMID: 36360212 PMCID: PMC9690299 DOI: 10.3390/genes13111976] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 01/07/2024] Open
Abstract
Breast cancer is one of the most common female malignancies worldwide. Due to its early metastases formation and a high degree of malignancy, the 10 year-survival rate of metastatic breast cancer does not exceed 30%. Thus, more precise biomarkers are urgently needed. In our study, we first estimated the tumor microenvironment (TME) infiltration using the xCell algorithm. Based on TME infiltration, the three main TME clusters were identified using consensus clustering. Our results showed that the three main TME clusters cause significant differences in survival rates and TME infiltration patterns (log-rank test, p = 0.006). Then, multiple machine learning algorithms were used to develop a nine-pathway-based TME-related risk model to predict the prognosis of breast cancer (BRCA) patients (the immune-related pathway-based risk score, defined as IPRS). Based on the IPRS, BRCA patients were divided into two subgroups, and patients in the IPRS-low group presented significantly better overall survival (OS) rates than the IPRS-high group (log-rank test, p < 0.0001). Correlation analysis revealed that the IPRS-low group was characterized by increases in immune-related scores (cytolytic activity (CYT), major histocompatibility complex (MHC), T cell-inflamed immune gene expression profile (GEP), ESTIMATE, immune, and stromal scores) while exhibiting decreases in tumor purity, suggesting IPRS-low patients may have a strong immune response. Additionally, the gene-set enrichment analysis (GSEA) result confirmed that the IPRS-low patients were significantly enriched in several immune-associated signaling pathways. Furthermore, multivariate Cox analysis revealed that the IPRS was an independent prognostic biomarker after adjustment by clinicopathologic characteristics. The prognostic value of the IPRS model was further validated in three external validation cohorts. Altogether, our findings demonstrated that the IPRS was a powerful predictor to screen out certain populations with better prognosis in breast cancer and may serve as a potential biomarker guiding clinical treatment decisions.
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Affiliation(s)
- Ji Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Jiayue Qiu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Junwei Han
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Xiangmei Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Ying Jiang
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin 150040, China
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25
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Abstract
ABSTRACT Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a pathologically similar disease used to model MS in rodents, are typical CD4+ T cell-dominated autoimmune diseases. CD4+ interleukin (IL)17+ T cells (Th17 cells) have been well studied and have shown that they play a critical role in the pathogenesis of MS/EAE. However, studies have suggested that CD8+IL17+ T cells (Tc17 cells) have a similar phenotype and cytokine and transcription factor profiles to those of Th17 cells and have been found to be crucial in the pathogenesis of autoimmune diseases, including MS/EAE, psoriasis, type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus. However, the evidence for this is indirect and insufficient. Therefore, we searched for related publications and attempted to summarize the current knowledge on the role of Tc17 cells in the pathogenesis of MS/EAE, as well as in the pathogenesis of other autoimmune diseases, and to find out whether Tc17 cells or Th17 cells play a more critical role in autoimmune disease, especially in MS and EAE pathogenesis, or whether the interaction between these two cell types plays a critical role in the development of the disease.
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Affiliation(s)
- Yong Peng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
| | - Xiang Deng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
| | - Qiuming Zeng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yandan Tang
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
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26
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Kudryavtsev IV, Arsentieva NA, Korobova ZR, Isakov DV, Rubinstein AA, Batsunov OK, Khamitova IV, Kuznetsova RN, Savin TV, Akisheva TV, Stanevich OV, Lebedeva AA, Vorobyov EA, Vorobyova SV, Kulikov AN, Sharapova MA, Pevtsov DE, Totolian AA. Heterogenous CD8+ T Cell Maturation and 'Polarization' in Acute and Convalescent COVID-19 Patients. Viruses 2022; 14:1906. [PMID: 36146713 PMCID: PMC9504186 DOI: 10.3390/v14091906] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The adaptive antiviral immune response requires interaction between CD8+ T cells, dendritic cells, and Th1 cells for controlling SARS-CoV-2 infection, but the data regarding the role of CD8+ T cells in the acute phase of COVID-19 and post-COVID-19 syndrome are still limited. METHODS . Peripheral blood samples collected from patients with acute COVID-19 (n = 71), convalescent subjects bearing serum SARS-CoV-2 N-protein-specific IgG antibodies (n = 51), and healthy volunteers with no detectable antibodies to any SARS-CoV-2 proteins (HC, n = 46) were analyzed using 10-color flow cytometry. RESULTS Patients with acute COVID-19 vs. HC and COVID-19 convalescents showed decreased absolute numbers of CD8+ T cells, whereas the frequency of CM and TEMRA CD8+ T cells in acute COVID-19 vs. HC was elevated. COVID-19 convalescents vs. HC had increased naïve and CM cells, whereas TEMRA cells were decreased compared to HC. Cell-surface CD57 was highly expressed by the majority of CD8+ T cells subsets during acute COVID-19, but convalescents had increased CD57 on 'naïve', CM, EM4, and pE1 2-3 months post-symptom onset. CXCR5 expression was altered in acute and convalescent COVID-19 subjects, whereas the frequencies of CXCR3+ and CCR4+ cells were decreased in both patient groups vs. HC. COVID-19 convalescents had increased CCR6-expressing CD8+ T cells. Moreover, CXCR3+CCR6- Tc1 cells were decreased in patients with acute COVID-19 and COVID-19 convalescents, whereas Tc2 and Tc17 levels were increased compared to HC. Finally, IL-27 negatively correlated with the CCR6+ cells in acute COVID-19 patients. CONCLUSIONS We described an abnormal CD8+ T cell profile in COVID-19 convalescents, which resulted in lower frequencies of effector subsets (TEMRA and Tc1), higher senescent state (upregulated CD57 on 'naïve' and memory cells), and higher frequencies of CD8+ T cell subsets expressing lung tissue and mucosal tissue homing molecules (Tc2, Tc17, and Tc17.1). Thus, our data indicate that COVID-19 can impact the long-term CD8+ T cell immune response.
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Affiliation(s)
- Igor V. Kudryavtsev
- Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Natalia A. Arsentieva
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Zoia R. Korobova
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Dmitry V. Isakov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Artem A. Rubinstein
- Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
| | - Oleg K. Batsunov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Irina V. Khamitova
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Raisa N. Kuznetsova
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Tikhon V. Savin
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
| | - Tatiana V. Akisheva
- Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
| | - Oksana V. Stanevich
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Smorodintsev Research Institute of Influenza, Prof. Popov St. 15/17, 197376 Saint Petersburg, Russia
| | - Aleksandra A. Lebedeva
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Evgeny A. Vorobyov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Snejana V. Vorobyova
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Alexander N. Kulikov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Maria A. Sharapova
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Dmitrii E. Pevtsov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Areg A. Totolian
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L’va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
- Laboratory of Immunology, Saint Petersburg Pasteur Institute, Mira 14, 197101 Saint Petersburg, Russia
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27
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Sun K, Xu R, Ma F, Yang N, Li Y, Sun X, Jin P, Kang W, Jia L, Xiong J, Hu H, Tian Y, Lan X. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nat Commun 2022; 13:4943. [PMID: 35999201 PMCID: PMC9399107 DOI: 10.1038/s41467-022-32627-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/10/2022] [Indexed: 11/15/2022] Open
Abstract
The tumor microenvironment (TME) in gastric cancer (GC) has been shown to be important for tumor control but the specific characteristics for GC are not fully appreciated. We generated an atlas of 166,533 cells from 10 GC patients with matched paratumor tissues and blood. Our results show tumor-associated stromal cells (TASCs) have upregulated activity of Wnt signaling and angiogenesis, and are negatively correlated with survival. Tumor-associated macrophages and LAMP3+ DCs are involved in mediating T cell activity and form intercellular interaction hubs with TASCs. Clonotype and trajectory analysis demonstrates that Tc17 (IL-17+CD8+ T cells) originate from tissue-resident memory T cells and can subsequently differentiate into exhausted T cells, suggesting an alternative pathway for T cell exhaustion. Our results indicate that IL17+ cells may promote tumor progression through IL17, IL22, and IL26 signaling, highlighting the possibility of targeting IL17+ cells and associated signaling pathways as a therapeutic strategy to treat GC. Gastric cancer can vary in tumour stage and immune cell involvement. Here the authors compare gene expression in immune cell types from the blood and the tumour site from GC patients using single cell and TCR sequencing and show that IL17+CD8+ T cells have a phenotype related to that seen with exhausted cells.
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Affiliation(s)
- Keyong Sun
- School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Runda Xu
- School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Fuhai Ma
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China.,Department of General Surgery, Department of Gastrointestinal Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, China
| | - Naixue Yang
- School of Medicine, Tsinghua University, 100084, Beijing, China.,Peking-Tsinghua-NIBS Joint Graduate Program, Tsinghua University, 100084, Beijing, China
| | - Yang Li
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China
| | - Xiaofeng Sun
- School of Medicine, Tsinghua University, 100084, Beijing, China.,Centre for Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Peng Jin
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China
| | - Wenzhe Kang
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China
| | - Lemei Jia
- School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Jianping Xiong
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China
| | - Haitao Hu
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China
| | - Yantao Tian
- Department of Pancreatic and Gastric Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, 100021, Beijing, China.
| | - Xun Lan
- School of Medicine, Tsinghua University, 100084, Beijing, China. .,Peking-Tsinghua-NIBS Joint Graduate Program, Tsinghua University, 100084, Beijing, China. .,Centre for Life Sciences, Tsinghua University, 100084, Beijing, China. .,MOE Key Laboratory of Bioinformatics, Tsinghua University, 100084, Beijing, China.
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28
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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29
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Inflammation and Gastric Cancer. Diseases 2022; 10:diseases10030035. [PMID: 35892729 PMCID: PMC9326573 DOI: 10.3390/diseases10030035] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer remains a major killer globally, although its incidence has declined over the past century. It is the fifth most common cancer and the third most common reason for cancer-related deaths worldwide. Gastric cancer is the outcome of a complex interaction between environmental, host genetic, and microbial factors. There is significant evidence supporting the association between chronic inflammation and the onset of cancer. This association is particularly robust for gastrointestinal cancers in which microbial pathogens are responsible for the chronic inflammation that can be a triggering factor for the onset of those cancers. Helicobacter pylori is the most prominent example since it is the most widespread infection, affecting nearly half of the world’s population. It is well-known to be responsible for inducing chronic gastric inflammation progressing to atrophy, metaplasia, dysplasia, and eventually, gastric cancer. This review provides an overview of the association of the factors playing a role in chronic inflammation; the bacterial characteristics which are responsible for the colonization, persistence in the stomach, and triggering of inflammation; the microbiome involved in the chronic inflammation process; and the host factors that have a role in determining whether gastritis progresses to gastric cancer. Understanding these interconnections may improve our ability to prevent gastric cancer development and enhance our understanding of existing cases.
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30
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Javadirad E, Sadeghi M, Oltulu P, Sadafi S. Associations of IL-4, IL-4R, IL-17A, and IL-17F Polymorphisms with Colorectal Cancer Risk: A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis. J Interferon Cytokine Res 2022; 42:203-219. [PMID: 35576490 DOI: 10.1089/jir.2021.0204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Both interleukin (IL)-4 and IL-17 polymorphisms may be involved in the pathogenesis and progression of colorectal cancer (CRC). Herein, we designed a meta-analysis to assess the associations between IL-4, IL-4R, IL-17A, and IL-17F polymorphisms and CRC risk. Scopus, Web of Science, Cochrane Library, and PubMed databases were searched to retrieve articles published until October 21, 2021. We used crude odds ratio (OR) and 95% confidence interval assessing the association of the polymorphisms and CRC risk in 5 genetic models. Trial sequential analysis for the primary analyses was used to control random errors. Twenty-three studies (8: IL-4 rs2243250, 4: IL-4R rs1801275, 5: IL-17A rs2275913, and 6: IL-17F rs763780) were involved in the meta-analysis. The pooled OR (P-value) for the association between IL-4 rs2243250 polymorphism and the CRC risk was 1.11 (0.08), 1.27 (0.12), 1.07 (0.37), 1.09 (0.17), and 1.22 (0.12), for IL-4R rs1801275 polymorphism was 0.71 (0.18), 1.05 (0.76), 0.86 (0.37), 0.87 (0.41), and 0.69 (0.39), for IL-17A rs2275913 polymorphism was 1.83 (0.0003), 1.73 (0.06), 1.47 (<0.001), 1.61 (0.001), and 1.42 (0.15), and for IL-17F rs763780 polymorphism was 1.07 (0.48), 5.33 (0.02), 1.08 (0.49), 1.08 (0.47), and 8.42 (0.002) in allelic, homozygous, heterozygous, recessive, and dominant models, respectively. The G allele and GA genotype of IL-17A rs2275913 polymorphism and the CC genotype of IL-17F rs763780 polymorphism had an elevated risk in CRC cases. The ethnicity and genotyping method, sample size, control, and publication year were effective factors on the pooled results.
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Affiliation(s)
- Etrat Javadirad
- Department of Pathology, Clinical Research Development Center, Medical School, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Sadeghi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pembe Oltulu
- Pathology Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Sepehr Sadafi
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
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31
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Li Y, Wang J, Wang H, Zhang S, Wei Y, Liu S. The Interplay Between Inflammation and Stromal Components in Pancreatic Cancer. Front Immunol 2022; 13:850093. [PMID: 35493517 PMCID: PMC9046560 DOI: 10.3389/fimmu.2022.850093] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/24/2022] [Indexed: 01/18/2023] Open
Abstract
Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.
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Affiliation(s)
- Ying Li
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Wang
- Department of Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiyan Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shaoqiang Zhang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yingxin Wei
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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32
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Peña-Romero AC, Orenes-Piñero E. Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers. Cancers (Basel) 2022; 14:1681. [PMID: 35406451 PMCID: PMC8996887 DOI: 10.3390/cancers14071681] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 02/04/2023] Open
Abstract
Our body is constantly exposed to pathogens or external threats, but with the immune response that our body can develop, we can fight off and defeat possible attacks or infections. Nevertheless, sometimes this threat comes from an internal factor. Situations such as the existence of a tumour also cause our immune system (IS) to be put on alert. Indeed, the link between immunology and cancer is evident these days, with IS being used as one of the important targets for treating cancer. Our IS is able to eliminate those abnormal or damaged cells found in our body, preventing the uncontrolled proliferation of tumour cells that can lead to cancer. However, in several cases, tumour cells can escape from the IS. It has been observed that immune cells, the extracellular matrix, blood vessels, fat cells and various molecules could support tumour growth and development. Thus, the developing tumour receives structural support, irrigation and energy, among other resources, making its survival and progression possible. All these components that accompany and help the tumour to survive and to grow are called the tumour microenvironment (TME). Given the importance of its presence in the tumour development process, this review will focus on one of the components of the TME: immune cells. Immune cells can support anti-tumour immune response protecting us against tumour cells; nevertheless, they can also behave as pro-tumoural cells, thus promoting tumour progression and survival. In this review, the anti-tumour and pro-tumour immunity of several immune cells will be discussed. In addition, the TME influence on this dual effect will be also analysed.
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Affiliation(s)
| | - Esteban Orenes-Piñero
- Department of Biochemistry and Molecular Biology-A, University of Murcia, 30120 Murcia, Spain;
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33
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Fang F, Zhang T, Li Q, Chen X, Jiang F, Shen X. The tumor immune-microenvironment in gastric cancer. TUMORI JOURNAL 2022; 108:541-551. [PMID: 35196917 DOI: 10.1177/03008916211070051] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS AND BACKGROUND The tumor microenvironment significantly influences malignant behavior and progression. Many components are involved in the tumor microenvironment, including extracellular matrix, stromal cells, immune and inflammatory cells, as well as cytokines that promote tumor development with complex interactions through the exchange of molecular information. It is now known that tumor immune escape may be influenced by the tumor microenvironment. The aim of this work is to conduct a review of the tumor immune-microenvironment in gastric cancer. METHODS We review the current knowledge of several immune cells involved in the gastric tumor microenvironment. In addition, a brief description of immunotherapy strategies for gastric cancer is also reviewed. CONCLUSIONS Among immune cell populations, lymphocytes, macrophages, dendritic cells and myeloid-derived suppressor cells are revealed to make the difference in promoting or suppressing gastric tumorigenesis, either directly or indirectly, via regulating the immune responses. Understanding these interactions in detail within the tumor immune-microenvironment will contribute to unraveling new therapeutic targets.
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Affiliation(s)
- Fujin Fang
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Tiantian Zhang
- Department of Clinical Laboratory, The Third People's Hospital of Bengbu, Bengbu, China
| | - Qiong Li
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Xiaowei Chen
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Fei Jiang
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Xiaobing Shen
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
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34
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Yang Y, Meng WJ, Wang ZQ. Cancer Stem Cells and the Tumor Microenvironment in Gastric Cancer. Front Oncol 2022; 11:803974. [PMID: 35047411 PMCID: PMC8761735 DOI: 10.3389/fonc.2021.803974] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide. Cancer stem cells (CSCs) might be responsible for tumor initiation, relapse, metastasis and treatment resistance of GC. The tumor microenvironment (TME) comprises tumor cells, immune cells, stromal cells and other extracellular components, which plays a pivotal role in tumor progression and therapy resistance. The properties of CSCs are regulated by cells and extracellular matrix components of the TME in some unique manners. This review will summarize current literature regarding the effects of CSCs and TME on the progression and therapy resistance of GC, while emphasizing the potential for developing successful anti-tumor therapy based on targeting the TME and CSCs.
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Affiliation(s)
| | - Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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35
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Ye JB, Wen JJ, Wu DL, Hu BX, Luo MQ, Lin YQ, Ning YS, Li Y. Elevated DLL3 in stomach cancer by tumor-associated macrophages enhances cancer-cell proliferation and cytokine secretion of macrophages. Gastroenterol Rep (Oxf) 2021; 10:goab052. [PMID: 35382168 PMCID: PMC8973010 DOI: 10.1093/gastro/goab052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 06/13/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
The notch signal pathway is important in the development of both tumor-associated macrophages (TAMs) and stomach cancer, but how Notch signaling affects TAMs in stomach cancer is barely understood.
Methods
The expressions of Notch1, Notch2, Notch3, Notch4, hes family bHLH transcription factor 1 (Hes1), and delta-like canonical Notch ligand 3 (DLL3) were detected by Western blot and the expressions of interleukin (IL)-10, IL-12, and IL1-β were detected using enzyme-linked immunosorbent assay after the co-culture of macrophages and stomach-cancer cells. The proliferation and migration of cancer cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and scratch assay, respectively, and the cell cycle was detected using Annexin V/propidium iodide assay. The protein interactions with DLL3 were detected using co-immunoprecipitation and mass spectrometry.
Results
The co-culture of macrophages and stomach-cancer cells MKN45 and BGC823 could enhance cell proliferation accompanied by the activation of Notch1/Notch2 signaling and upregulation of DLL3. Notch signaling gamma-secretase inhibitor (DAPT) blocked this process. The overexpression of DLL3 in stomach-cancer cells could promote the proliferation of cancer cells, enhance the activation of Notch1/Notch2 signaling, induce the expression of IL-33, lead to the degradation of galectin-3–binding protein (LG3BP) and heat shock cognate 71 kDa protein (HSPA8), and result in elevated IL-1β, IL-12, and IL-10 secretion by macrophages. Higher expression of DLL3 or IL-33 could lead to a lower survival rate based on University of California, Santa Cruz Xena Functional Genomics Explorer and The Cancer Genome Atlas data set.
Conclusions
This is evidence that DLL3 regulates macrophages in stomach cancer, suggesting that DLL3 may be a novel and potential target for stomach-cancer therapy.
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Affiliation(s)
- Jian-Bin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Jun-Jie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Dan-Lin Wu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Bing-Xin Hu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Mei-Qun Luo
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yan-Qing Lin
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yun-Shan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Service Union Medicine, Southern Medical University, Zhuhai, Guangdong, P.R. China
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, P.R. China
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36
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Kim DH, Kim HY, Lee WW. Induction of Unique STAT Heterodimers by IL-21 Provokes IL-1RI Expression on CD8 + T Cells, Resulting in Enhanced IL-1β Dependent Effector Function. Immune Netw 2021; 21:e33. [PMID: 34796037 PMCID: PMC8568912 DOI: 10.4110/in.2021.21.e33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/11/2021] [Accepted: 08/23/2021] [Indexed: 12/24/2022] Open
Abstract
IL-1β plays critical roles in the priming and effector phases of immune responses such as the differentiation, commitment, and memory formation of T cells. In this context, several reports have suggested that the IL-1β signal is crucial for CTL-mediated immune responses to viral infections and tumors. However, little is known regarding whether IL-1β acts directly on CD8+ T cells and what the molecular mechanisms underlying expression of IL-1 receptors (IL-1Rs) on CD8+ T cells and features of IL-1R+CD8+ T cells are. Here, we provide evidence that the expression of IL-1R type I (IL-1RI), the functional receptor of IL-1β, is preferentially induced by IL-21 on TCR-stimulated CD8+ T cells. Further, IL-1β enhances the effector function of CD8+ T cells expressing IL-21-induced IL-1RI by increasing cytokine production and release of cytotoxic granules containing granzyme B. The IL-21-IL-1RI-IL-1β axis is involved in an augmented effector function through regulation of transcription factors BATF, Blimp-1, and IRF4. Moreover, this axis confers a unique effector function to CD8+ T cells compared to conventional type 1 cytotoxic T cells differentiated with IL-12. Chemical inhibitor and immunoprecipitation assay demonstrated that IL-21 induces a unique pattern of STAT activation with the formation of both STAT1:STAT3 and STAT3:STAT5 heterodimers, which are critical for the induction of IL-1RI on TCR-stimulated CD8+ T cells. Taken together, we propose that induction of a novel subset of IL-1RI-expressing CD8+ T cells by IL-21 may be beneficial to the protective immune response against viral infections and is therefore important to consider for vaccine design.
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Affiliation(s)
- Dong Hyun Kim
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hee Young Kim
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea.,Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Won-Woo Lee
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea.,Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Korea.,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.,Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea
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Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, Bhutkar A, Canner D, Kienka T, Tavana SZ, Barandiaran AL, Garmilla A, Schenkel JM, Hillman M, de Los Rios Kobara I, Li A, Jaeger AM, Hwang WL, Westcott PMK, Manos MP, Holovatska MM, Hodi FS, Regev A, Santagata S, Jacks T. Antigen dominance hierarchies shape TCF1 + progenitor CD8 T cell phenotypes in tumors. Cell 2021; 184:4996-5014.e26. [PMID: 34534464 PMCID: PMC8522630 DOI: 10.1016/j.cell.2021.08.020] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2021] [Accepted: 08/16/2021] [Indexed: 12/14/2022]
Abstract
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.
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Affiliation(s)
- Megan L Burger
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Amanda M Cruz
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Grace E Crossland
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Giorgio Gaglia
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Cecily C Ritch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Sarah E Blatt
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Arjun Bhutkar
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - David Canner
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Tamina Kienka
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Sara Z Tavana
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Alexia L Barandiaran
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Andrea Garmilla
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jason M Schenkel
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michelle Hillman
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Izumi de Los Rios Kobara
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Amy Li
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Alex M Jaeger
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - William L Hwang
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Peter M K Westcott
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Michael P Manos
- Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
| | - Marta M Holovatska
- Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
| | - F Stephen Hodi
- Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
| | - Aviv Regev
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Sandro Santagata
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02215, USA
| | - Tyler Jacks
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Sun L, Ko J, Vidimos A, Koyfman S, Gastman B. A Distinctive Lineage-Negative Cell Population Produces IL-17A in Cutaneous Squamous Cell Carcinoma. J Interferon Cytokine Res 2021; 40:418-424. [PMID: 32813604 DOI: 10.1089/jir.2020.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Interleukin (IL)-17A is a key proinflammatory cytokine indicated in multiple pathologies, including skin tumorigenesis. While IL-17A is a signature cytokine of Th17 cells, IL-17A is also produced by other cell types, including type 3 innate lymphoid cells (ILC3s) in the skin, particularly in patients with psoriasis. Interestingly, we detect CD45+Lin-(CD3-CD14-CD19-CD20-) IL-17A+ cells in the cutaneous squamous cell carcinomas (cSCCs) by flow cytometry of the cell suspensions prepared from tumor tissues. Consistently, we found CD3-IL-17+ cells in tumor tissue of skin cSCCs by immunohistochemistry staining of serial sections of SCCs from both immunocompetent and immunocompromised patients (e.g., transplant patients on iatrogenic long-term immunosuppressive therapy). In several immunocompromised patients, the CD3-IL-17+ cells consist of over 90% of the total IL-17+ cells in the tumor tissue. Furthermore, these CD3-IL-17+ cells are negatively stained for SMA, CD11b, and CD19, suggesting that they are unlikely to be fibroblast, myeloid cells, or B cells. Taken together, we found a population of lineage-negative IL-17A-producing cells present in the cSCCs, which share the "CD45+Lin-" features with ILCs. This study suggests that IL-17A can be produced by immune cell populations other than T cells in skin SCCs.
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Affiliation(s)
- Lillian Sun
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Jennifer Ko
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA.,Department of Anatomical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Allison Vidimos
- Department of Dermatology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Shlomo Koyfman
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Brian Gastman
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA.,Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Iwamuro M, Takahashi T, Watanabe N, Okada H. Isolation of lymphocytes from the human gastric mucosa. World J Methodol 2021; 11:199-207. [PMID: 34322369 PMCID: PMC8299908 DOI: 10.5662/wjm.v11.i4.199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 04/09/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Flow cytometry is widely used for lymphocyte immunophenotyping in clinical settings. However, few studies have applied it for analyzing lymphocytes of the gastric mucosa. This review offers an overview of methodologies for isolating lymphocytes from the human stomach. Previously reported articles were reviewed, focusing on procedures for isolating human gastric mucosal lymphocytes. Helicobacter pylori-associated peptic diseases and gastric cancer are two major subjects of research in this field. Enzymatic dissociation, mechanical dissociation, or a combination of the two have been used to isolate lymphocytes from the stomach. Intra-epithelial and lamina propria lymphocytes were separately isolated in several studies. We also summarize the history and present trends in analyzing lymphocytes in patients with gastric disease.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Takahide Takahashi
- Division of Medical Support, Okayama University Hospital, Okayama 700-8558, Japan
| | - Natsuki Watanabe
- Division of Medical Support, Okayama University Hospital, Okayama 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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40
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Shan Z, Chen J, Liu J, Zhang J, Wang T, Teng Y, Mao F, Cheng P, Zou Q, Zhou W, Peng L, Zhao Y, Zhuang Y. Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer. Clin Transl Med 2021; 11:e484. [PMID: 34185422 PMCID: PMC8236123 DOI: 10.1002/ctm2.484] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/12/2021] [Accepted: 06/16/2021] [Indexed: 01/09/2023] Open
Abstract
RATIONALE Neutrophils constitute massive cellular constituents in inflammatory human gastric cancer (GC) tissues, but their roles in pathogenesis of inflammatory T helper (Th) subsets are still unknown. METHODS Flow cytometry analysis and immunohistochemistry were used to analyze the responses and phenotypes of neutrophils in different samples from 51 patients with GC. Kaplan-Meier plots and Multivariate analysis for the survival of patients were used by log-rank tests and Cox proportional hazards models. Neutrophils and CD4+ T cells were purified and cultured for ex vivo, in vitro and in vivo regulation and function assays. RESULTS GC patients exhibited increased tumoral neutrophil infiltration with GC progression and poor patient prognosis. Intratumoral neutrophils accumulated in GC tumors via CXCL6/CXCL8-CXCR1-mediated chemotaxis, and expressed activated molecule CD54 and co-signaling molecule B7-H2. Neutrophils induced by tumors strongly expressed CD54 and B7-H2 in both dose- and time-dependent manners, and a close correlation was obtained between the expressions of CD54 and B7-H2 on intratumoral neutrophils. Tumor-derived tumor necrosis factor-α (TNF-α) promoted neutrophil activation and neutrophil B7-H2 expression through ERK-NF-κB pathway, and a significant correlation was found between the levels of TNF-α and CD54+ or B7-H2+ neutrophils in tumor tissues. Tumor-infiltrating and tumor-conditioned neutrophils effectively induced IL-17A-producing Th subset polarization through a B7-H2-dependent manner ex vivo and these polarized IL-17A-producing Th cells exerted protumorigenic roles by promoting GC tumor cell proliferation via inflammatory molecule IL-17A in vitro, which promoted the progression of human GC in vivo; these effects could be reversed when IL-17A is blocked. Moreover, increased B7-H2+ neutrophils and IL-17A in tumors were closely related to advanced GC progression and predicted poor patient survival. CONCLUSION We illuminate novel underlying mechanisms that TNF-α-activated neutrophils link B7-H2 to protumorigenic IL-17A-producing Th subset polarization in human GC. Blocking this pathological TNF-α-B7-H2-IL-17A pathway may be useful therapeutic strategies for treating GC.
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Affiliation(s)
- Zhi‐guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqingChina
| | - Jun Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqingChina
| | - Jin‐shan Liu
- Department of General SurgeryQijiang Hospital of the First Affiliated Hospital of Chongqing Medical UniversityQijiangChongqingChina
| | - Jin‐yu Zhang
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Ting‐ting Wang
- Chongqing Key Research Laboratory for Drug MetabolismDepartment of PharmacologyChongqing Medical UniversityChongqingChina
| | - Yong‐sheng Teng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Fang‐yuan Mao
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Ping Cheng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Quan‐ming Zou
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Wei‐ying Zhou
- Chongqing Key Research Laboratory for Drug MetabolismDepartment of PharmacologyChongqing Medical UniversityChongqingChina
| | - Liu‐sheng Peng
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
| | - Yong‐liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal SurgerySouthwest HospitalThird Military Medical UniversityChongqingChina
| | - Yuan Zhuang
- National Engineering Research Center of Immunological ProductsDepartment of Microbiology and Biochemical PharmacyCollege of PharmacyThird Military Medical UniversityChongqingChina
- Department of Gastroenterology the Affiliated Hospital of Southwest Medical UniversityLuzhouSichuanChina
- Jiangsu Key Laboratory of Medical Science and Laboratory MedicineSchool of MedicineJiangsu UniversityJiangsuChina
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Li ZY, Wang JT, Chen G, Shan ZG, Wang TT, Shen Y, Chen J, Yan ZB, Peng LS, Mao FY, Teng YS, Liu JS, Zhou YY, Zhao YL, Zhuang Y. Expression, regulation and clinical significance of B7-H3 on neutrophils in human gastric cancer. Clin Immunol 2021; 227:108753. [PMID: 33945871 DOI: 10.1016/j.clim.2021.108753] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H3+ neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3+ neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3+ neutrophils to be potential biomarkers in GC.
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Affiliation(s)
- Zheng-Yan Li
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jin-Tao Wang
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Gang Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhi-Guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ting-Ting Wang
- Chongqing Key Research Laboratory for Drug Metabolism, Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yang Shen
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jun Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zong-Bao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Jin-Shan Liu
- Department of General Surgery, Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University, Qijiang, Chongqing, China
| | - Yuan-Yuan Zhou
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China.
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Koemans WJ, van Dieren JM, van den Berg JG, Meijer GA, Snaebjornsson P, Chalabi M, Lecot F, Riedl R, Krijgsman O, Hofland I, Broeks A, Voncken FEM, Peppelenbosch MP, Sosef MN, van Sandick JW, Kodach LL. High CD8 + tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy. Histopathology 2021; 79:238-251. [PMID: 33660299 DOI: 10.1111/his.14361] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 02/04/2021] [Accepted: 03/02/2021] [Indexed: 11/29/2022]
Abstract
AIMS Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. METHODS AND RESULTS The prognostic significance of OAC-associated CD3+ , CD4+ , CD8+ , forkhead box protein 3 (FoxP3+ ) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). CONCLUSION A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.
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Affiliation(s)
- Willem J Koemans
- Department of Surgical Oncology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jolanda M van Dieren
- Department of Gastrointestinal Oncology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jose G van den Berg
- Department of Pathology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Gerrit A Meijer
- Department of Pathology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Petur Snaebjornsson
- Department of Pathology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Myriam Chalabi
- Department of Gastrointestinal Oncology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Frederig Lecot
- Department of Surgery, Zuyderland Hospital, Heerlen, the Netherlands
| | - Robert Riedl
- Department of Pathology, Zuyderland Hospital, Heerlen, the Netherlands
| | - Oscar Krijgsman
- Departments of Molecular Oncology and Immunology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Ingrid Hofland
- Departments of Core Facility, Molecular Pathology and Biobanking, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Annegien Broeks
- Departments of Core Facility, Molecular Pathology and Biobanking, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Francine E M Voncken
- Department of Radiotherapy, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Departments of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Meindert N Sosef
- Department of Surgery, Zuyderland Hospital, Heerlen, the Netherlands
| | - Johanna W van Sandick
- Department of Surgical Oncology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Liudmila L Kodach
- Department of Pathology, Antoni van Leeuwenhoek, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Screening of immunosuppressive cells from colorectal adenocarcinoma and identification of prognostic markers. Biosci Rep 2021; 41:228002. [PMID: 33646276 PMCID: PMC8024875 DOI: 10.1042/bsr20203496] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Colorectal cancer (CRC) is the most common type of gastrointestinal malignant tumour. Colorectal adenocarcinoma (COAD) – the most common type of CRC – is particularly dangerous. The role of the immune system in the development of tumour-associated inflammation and cancer has received increasing attention recently. Methods: In the present study, we compiled the expression profiles of 262 patients with complete follow-up data from The Cancer Genome Atlas (TCGA) database as an experimental group and selected 65 samples from the Gene Expression Omnibus (GEO) dataset (of which 46 samples were with M0) as a verification group. First, we screened the immune T helper 17 (Th17) cells related to the prognosis of COAD. Subsequently, we identified Th17 cells-related hub genes by utilising Weighted Gene Co-expression Network Analysis (WGCNA) and Least Absolute Shrinkage and Selector Operation (LASSO) regression analysis. Six genes associated with the prognosis in patients with COAD were identified, including: KRT23, ULBP2, ASRGL1, SERPINA1, SCIN, and SLC28A2. We constructed a clinical prediction model and analysed its predictive power. Results: The identified hub genes are involved in developing many diseases and closely linked to digestive disorders. Our results suggested that the hub genes could influence the prognosis of COAD by regulating Th17 cells’ infiltration. Conclusions: These newly discovered hub genes contribute to clarifying the mechanisms of COAD development and metastasis. Given that they promote COAD development, they may become new therapeutic targets and biomarkers of COAD.
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Jing Y, Xu F, Liang W, Liu J, Zhang L. Role of regulatory B cells in gastric cancer: Latest evidence and therapeutics strategies. Int Immunopharmacol 2021; 96:107581. [PMID: 33812259 DOI: 10.1016/j.intimp.2021.107581] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022]
Abstract
Gastric cancer (GC) is the second most common cancer globally and kills about 700,000 people annually. Today's knowledge clearly shows a close and complicated relationship between the tumor microenvironment (TME) and the immune system. The immune system components can both stimulate tumor growth and inhibit tumor cells. However, numerous of these mechanisms are not yet fully understood. As an essential immune cell in humoral immunity, B lymphocytes can play a dual role during various pathologic states, including infections, autoimmune diseases, and cancer, depending on their phenotype and environmental signals. Inherently, B cells can inhibit tumor growth by producing antibodies as well as the presentation of tumor antigens. However, evidence suggests that a subset of these cells termed regulatory B cells (Bregs) with an inhibitory phenotype can suppress anti-tumor responses and support the tumor growth by producing anti-inflammatory cytokines and the expression of inhibitory molecules. Therefore, in this review, the role of Bregs in the microenvironment of GC and treatment strategies based on targeting this subset of B cells have been investigated.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
| | - Fangming Xu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan 316000, Zhejiang Province, PR China
| | - Jian Liu
- Department of Hepatobiliary Surgery, Shanghai Oriental Hepatobiliary Hospital, Shanghai 200438, PR China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, PR China.
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Cui C, Lan P, Fu L. The role of myeloid-derived suppressor cells in gastrointestinal cancer. Cancer Commun (Lond) 2021; 41:442-471. [PMID: 33773092 PMCID: PMC8211353 DOI: 10.1002/cac2.12156] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/09/2021] [Accepted: 03/10/2021] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) cancer encompasses a range of malignancies that originate in the digestive system, which together represent the most common form of cancer diagnosed worldwide. However, despite numerous advances in both diagnostics and treatment, the incidence and mortality rate of GI cancer are on the rise. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions, such as infection and inflammation, and this expansion is of particular relevance to cancer. MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors, favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence. Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patients with cancer, and potentially as a novel treatment target. In the present review, the mechanisms underlying the immunosuppressive functions of MDSCs are described, and recent researches concerning the involvement of MDSCs in the progression, prognosis, and therapies of GI cancer are reviewed. The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.
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Affiliation(s)
- Cheng Cui
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Centre, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518055, P. R. China
| | - Penglin Lan
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Centre, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518055, P. R. China
| | - Li Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Centre, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518055, P. R. China
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Wang X, Chen H, Jiang R, Hong X, Peng J, Chen W, Jiang J, Li J, Huang D, Dai H, Wang W, Lu J, Zhao Y, Wu W. Interleukin-17 activates and synergizes with the notch signaling pathway in the progression of pancreatic ductal adenocarcinoma. Cancer Lett 2021; 508:1-12. [PMID: 33713738 DOI: 10.1016/j.canlet.2021.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 02/27/2021] [Accepted: 03/03/2021] [Indexed: 12/28/2022]
Abstract
Interleukin (IL)-17 is a prominent cytokine that promotes pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and is associated with the oncogenic pathways in tumor progression. However, the mechanism and therapeutic value of the IL-17 axis remain unclear. In this study, we verified the activation of the IL-17 and Notch pathways in PanIN/PDAC via complementary approaches and validated their pro-tumor effects on tumor progression. Additionally, we found a positive correlation between IL-17 and Notch; the IL-17 axis can upregulate Notch activity via the canonical NF-κB pathway in vitro, thus synergistically promoting PanIN/PDAC. Furthermore, we observed that the co-inhibition of IL-17 and the Notch pathway can enhance the therapeutic effect by restricting tumor growth in vivo. Our study highlights the synergistic effect of the IL-17 axis and Notch pathway in promoting PanIN/PDAC and further suggests that IL-17-Notch co-inhibition is a novel therapeutic strategy with superior potential in treating PDAC.
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Affiliation(s)
- Xianze Wang
- Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Hao Chen
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Rui Jiang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xiafei Hong
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Junya Peng
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Wenyan Chen
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Jialin Jiang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Jie Li
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Dan Huang
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Hongmei Dai
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Wenze Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Junliang Lu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Yupei Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Wenming Wu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
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Granulocyte-Macrophage Colony-Stimulating Factor-Activated Neutrophils Express B7-H4 That Correlates with Gastric Cancer Progression and Poor Patient Survival. J Immunol Res 2021; 2021:6613247. [PMID: 33763491 PMCID: PMC7962878 DOI: 10.1155/2021/6613247] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/07/2021] [Accepted: 02/13/2021] [Indexed: 02/07/2023] Open
Abstract
Neutrophils are prominent components of gastric cancer (GC) tumors and exhibit distinct phenotypes in GC environment. However, the phenotype, regulation, and clinical relevance of neutrophils in human GC are presently unknown. Here, immunohistochemistry, real-time PCR, and flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 41 patients with GC, and also isolated, stimulated, and/or cultured neutrophils for in vitro regulation assays. Finally, we performed Kaplan-Meier plots for overall survival by using the log-rank test to evaluate the clinical relevance of neutrophils and their subsets. In our study, neutrophils in tumor tissues were significantly higher than those in nontumor tissues and were positively associated with tumor progression but negatively correlated with GC patient survival. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high-level immunosuppressive molecule B7-H4. Tumor tissue culture supernatants from GC patients induced neutrophils to express CD54 and B7-H4 in both time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H4+ neutrophils positively correlated with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) detection ex vivo, and in vitro GM-CSF induced the expression of CD54 and B7-H4 on neutrophils in a time-dependent and dose-dependent manner. Moreover, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H4 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway activation. Furthermore, higher intratumoral B7-H4+ neutrophil percentage/number was found in GC patients with advanced tumor node metastasis stage and reduced overall survival following surgery. Our results illuminate a novel regulating mechanism of B7-H4 expression on tumor-activated neutrophils in GC, suggesting that functional inhibition of these novel GM-CSF-B7-H4 pathways may be a suitable therapeutic strategy to treat the immune tolerance feature of GC.
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Abstract
The IL-17 family is an evolutionarily old cytokine family consisting of six members (IL-17A through IL-17F). IL-17 family cytokines signal through heterodimeric receptors that include the shared IL-17RA subunit, which is widely expressed throughout the body on both hematopoietic and nonhematopoietic cells. The founding family member, IL-17A, is usually referred to as IL-17 and has received the most attention for proinflammatory roles in autoimmune diseases like psoriasis. However, IL-17 is associated with a wide array of diseases with perhaps surprisingly variable pathologies. This review focuses on recent advances in the roles of IL-17 during health and in disease pathogenesis. To decipher the functions of IL-17 in diverse disease processes it is useful to first consider the physiological functions that IL-17 contributes to health. We then discuss how these beneficial functions can be diverted toward pathogenic amplification of deleterious pathways driving chronic disease.
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Affiliation(s)
- Saikat Majumder
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania 15261, USA; ,
| | - Mandy J McGeachy
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania 15261, USA; ,
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Jan I, Rather RA, Mushtaq I, Malik AA, Besina S, Baba AB, Farooq M, Yousuf T, Rah B, Afroze D. Helicobacter pylori Subdues Cytokine Signaling to Alter Mucosal Inflammation via Hypermethylation of Suppressor of Cytokine Signaling 1 Gene During Gastric Carcinogenesis. Front Oncol 2021; 10:604747. [PMID: 33569347 PMCID: PMC7868987 DOI: 10.3389/fonc.2020.604747] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/07/2020] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori infection has been associated with the onset of gastric mucosal inflammation and is known to perturb the balance between T-regulatory (Treg) and T-helper 17 (Th17) cells which causes a spurt of interleukin 17 (IL17) and transforming growth factor-β (TGF-β) from Th17 and Treg cells within the gastric milieu. IL17 instigates a surge of interleukin 6 (IL6) from T-helper 1 (Th1) and T-helper 2 (Th2) cells. Further, H. pylori infection is known to stimulate the atypical DNA methylation in gastric mucosa. However, the precise role of cytokine signaling in induction of epigenetic modifications during gastric carcinogenesis is vaguely understood. In this study, patient samples from were examined using real-time polymerase chain reaction (qPCR), PCR, methylation-specific (MS)-PCR, and enzyme-linked immunosorbent assays. We found that H. pylori infection augments the production of interleukin 10 (IL10), IL6, and TGF-β in the gastric milieu and systemic circulation. Together with the IL6/IL10 mediated hyperactivation of the JAK/STAT pathway, H. pylori infection causes the inactivation of suppressor of cytokine signaling 1 (SOCS1) gene through the hypermethylation of the promoter region. This study signifies that H. pylori-mediated epigenetic silencing of SOCS1 in concert with inflammatory cytokines miffs hyperactivation of the JAK/STAT cascade during gastric carcinogenesis.
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Affiliation(s)
- Iqra Jan
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Rafiq A Rather
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Ifra Mushtaq
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Ajaz A Malik
- Department of General and Minimal Invasive Surgery, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Syed Besina
- Department of Pathology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Abdul Basit Baba
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Muzamil Farooq
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Tahira Yousuf
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Bilal Rah
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Dil Afroze
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.,Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
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50
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Huang Y, Chen L, Tang Z, Min Y, Yu W, Yang G, Zhang L. A Novel Immune and Stroma Related Prognostic Marker for Invasive Breast Cancer in Tumor Microenvironment: A TCGA Based Study. Front Endocrinol (Lausanne) 2021; 12:774244. [PMID: 34867821 PMCID: PMC8636929 DOI: 10.3389/fendo.2021.774244] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/01/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most frequent cancer in women. The tumor microenvironment (TME), consisting of blood vessels, immune cells, fibroblasts, and extracellular matrix, plays a pivotal role in tumorigenesis and progression. Increasing evidence has emphasized the importance of TME, especially the immune components, in patients with BC. Nevertheless, we still lack a deep understanding of the correlation between tumor invasion and TME status. METHODS Transcriptome and clinical data were retrieved from The Cancer Genome Atlas (TCGA) database. ESTIMATE algorithm was applied for quantifying stromal and immune scores. Then we screened out the differentially expressed genes (DEGs) through the intersection analysis. Furthermore, the establishment of protein-protein interaction (PPI) network and univariate COX regression analysis were utilized to determine the core genes in DEGs. In addition, we also performed Gene Set Enrichment Analysis (GSEA) and CIBERSORT analysis to distinguish the function of crucial gene expression and the proportion of tumor-infiltrating immune cells (TICs), respectively. RESULTS A total of 1178 samples (112 normal samples and 1066 tumor samples) were extracted from TCGA for calculation, and 226 DEGs were obtained from this assessment. Further intersection analysis revealed eight key genes, including ITK, CD3E, CCL19, CD2, SH2D1A, CD5, SLAMF6, SPN, which were proven to correlate with BC status. Moreover, ITK was picked out for further study. The results illustrated that high expression of BC patients had a more prolonged overall survival (OS) time than ITK low expression BC patients (p = 0.009), and ITK expression also presented the statistical significance in age, TNM staging, tumor size classification, and metastasis classification. Additionally, GSEA and CIBERSORT analysis indicated that ITK expression had an association with immune activity in TME. CONCLUSION ITK may be a potential indicator for prognosis prediction in patients with BC, and its biological behavior may promote our understanding of the molecular mechanism of tumor progression and targeted therapy.
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Affiliation(s)
- Yizhou Huang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lizhi Chen
- College of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ziyi Tang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Min
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wanli Yu
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Lili Zhang, ; Gangyi Yang,
| | - Lili Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Lili Zhang, ; Gangyi Yang,
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