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Li X, Hou W, Xiao C, Yang H, Zhao C, Cao D. Panoramic tumor microenvironment in pancreatic ductal adenocarcinoma. Cell Oncol (Dordr) 2024; 47:1561-1578. [PMID: 39008192 DOI: 10.1007/s13402-024-00970-6] [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] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance to various treatment modalities. The genetic heterogeneity of PDAC, coupled with the presence of a desmoplastic stroma within the tumor microenvironment (TME), contributes to an unfavorable prognosis. The mechanisms and consequences of interactions among different cell types, along with spatial variations influencing cellular function, potentially play a role in the pathogenesis of PDAC. Understanding the diverse compositions of the TME and elucidating the functions of microscopic neighborhoods may contribute to understanding the immune microenvironment status in pancreatic cancer. As we delve into the spatial biology of the microscopic neighborhoods within the TME, aiding in deciphering the factors that orchestrate this intricate ecosystem. This overview delineates the fundamental constituents and the structural arrangement of the PDAC microenvironment, highlighting their impact on cancer cell biology.
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Affiliation(s)
- Xiaoying Li
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Wanting Hou
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chaoxin Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Heqi Yang
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Dan Cao
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China.
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Mishra S, Telang G, Bennur D, Chougule S, Dandge PB, Joshi S, Vyas N. T Cell Exhaustion and Activation Markers in Pancreatic Cancer: A Systematic Review. J Gastrointest Cancer 2024; 55:77-95. [PMID: 37672169 DOI: 10.1007/s12029-023-00965-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND T cell exhaustion and activation markers are helpful in determining the therapies and predicting the overall survival in pancreatic cancer (PC) patients. PURPOSE In this systematic review, we have addressed two questions, how do these markers differ in their expression levels in PC patients and healthy individual and correlating the expression level of these markers with the cancer stage. METHODS The systematic review was registered with Prospective Register of Systematic Reviews (PROSPERO) with registration number "CRD42022246780." All the included articles were obtained from three databases, PubMed, MEDLINE, and Cochrane, published from January 2010 to 26th May 2022. Two independent reviewers followed the PRISM protocol and reviewed and extracted data from the included articles. RESULTS PD-1 and CTLA-4 were the most studied markers in this field. A clear elevation in the expression of PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT was found in most of the studies. CD69, CD25, and HLA-DR expression was found to be upregulated after chemotherapy and immunotherapy. CD25 was the only marker analyzed against cancer progression, in a single study. No study compared the expression of exhaustion and activation markers (except CD69) with the cancer progression of the tumor stage. CONCLUSION Since the exhaustion markers are upregulated in patients, single or multiple markers can be targeted in immunotherapies. Knowledge of the dynamics of these markers at various cancer stages will help in determining the right immunotherapy for pancreatic cancer patients. Stage-wise comparison could also be made possible by developing in vitro models.
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Affiliation(s)
- Smriti Mishra
- Logical Life Science Pvt. Ltd., Pune, 411041, Maharashtra, India
| | - Gaurang Telang
- Logical Life Science Pvt. Ltd., Pune, 411041, Maharashtra, India
| | - Darpan Bennur
- Logical Life Science Pvt. Ltd., Pune, 411041, Maharashtra, India
| | - Shruti Chougule
- Logical Life Science Pvt. Ltd., Pune, 411041, Maharashtra, India
| | - P B Dandge
- Department of Biochemistry, Shivaji University, Kolhapur, 416004, Maharashtra, India
| | - Shantanu Joshi
- Acuere Biosciences Pvt. Ltd., Pune, 411043, Maharashtra, India
| | - Nishant Vyas
- Logical Life Science Pvt. Ltd., Pune, 411041, Maharashtra, India.
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Joseph AM, Al Aiyan A, Al-Ramadi B, Singh SK, Kishore U. Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front Immunol 2024; 15:1323198. [PMID: 38384463 PMCID: PMC10879611 DOI: 10.3389/fimmu.2024.1323198] [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: 10/17/2023] [Accepted: 01/11/2024] [Indexed: 02/23/2024] Open
Abstract
One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance. Furthermore, an extensive desmoplastic stroma that surrounds PDAC forms a mechanical barrier that prevents vascularization and promotes poor immune cell penetration. Phenotypic heterogeneity, drug resistance, and immunosuppressive tumor microenvironment are the main causes of PDAC aggressiveness. There is a complex and dynamic interaction between tumor cells in PDAC with stromal cells within the tumour immune microenvironment. The immune suppressive microenvironment that promotes PDAC aggressiveness is contributed by a range of cellular and humoral factors, which itself are modulated by the cancer. In this review, we describe the role of innate and adaptive immune cells, complex tumor microenvironment in PDAC, humoral factors, innate immune-mediated therapeutic advances, and recent clinical trials in PDAC.
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Affiliation(s)
- Ann Mary Joseph
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ahmad Al Aiyan
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Basel Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Shiv K. Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, Goettingen, Germany
| | - Uday Kishore
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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4
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Xie D, Tian Y, Hu D, Wang Y, Yang Y, Zhou B, Zhang R, Ren Z, Liu M, Xu J, Dong C, Zhao B, Yang L. Oncolytic adenoviruses expressing checkpoint inhibitors for cancer therapy. Signal Transduct Target Ther 2023; 8:436. [PMID: 38016957 PMCID: PMC10684539 DOI: 10.1038/s41392-023-01683-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 09/22/2023] [Accepted: 10/17/2023] [Indexed: 11/30/2023] Open
Abstract
Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+ T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
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Affiliation(s)
- Daoyuan Xie
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yaomei Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- College of Bioengineering, Sichuan University of Science & Engineering, Zigong, 643000, China
| | - Die Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuanda Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuling Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bailing Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhixiang Ren
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mohan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jie Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunyan Dong
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Binyan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
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Yang J, Meng L, Yang Y, Gao H, Jiang H. Elevated programmed cell death-1 protein/ligand (PD-1/PD-L1) and variants are associated with susceptibility to multiple myeloma: a case-control study in the Chinese cohort. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:230-248. [PMID: 37688463 DOI: 10.1080/15257770.2023.2253276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/14/2023] [Accepted: 08/24/2023] [Indexed: 09/11/2023]
Abstract
Multiple myeloma (MM) is a malignant disorder characterised by progressive immune dysregulation. The importance of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) in MM has been documented in various populations, but studies have been limited to the Chinese cohort. In the present study, we examined the role of PD-1/PDL-1 in large cohorts of Chinese patients with MM and healthy controls to reveal a possible association with MM. Three hundred thirty-four MM patients and 202 healthy age-sex-matched subjects were enrolled in the present study. Serum levels of PD-1 and PD-L1 were quantified by ELISA. Percentages of T cells (CD4+ and CD8+ T cells) expressing PD-1 receptor were assessed by flow cytometry. Variants in PD-L1 (rs4143815) and PD-1 gene (rs2227981, rs2227982, rs7421861 and rs11568821) were genotyped by PCR-RFLP method. Patients with multiple myeloma had higher levels of PD-1 and PDL-1 than healthy controls, indicating an important role for programmed cell death protein-1 and its ligand in the pathogenesis of MM. T cells expressing PD-1 receptors were also significantly higher in MM patients than in controls. Mutants for PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) polymorphisms were significantly more common in MM than in HC. Interestingly, PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) variants were linked to higher sPD-L1 and sPD-1 levels, respectively. PD-1/PD-L1 levels are significantly higher in MM patients and could be a promising biomarker for the disease. Variants of PD-L1 and PD-1 are linked to serum-soluble proteins and are associated with the development of MM.
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Affiliation(s)
- Jing Yang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Ling Meng
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yongxin Yang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Honggang Jiang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Lu M, Zou Y, Fu P, Li Y, Wang P, Li G, Luo S, Chen Y, Guan G, Zhang S, Chen L. The tumor-stroma ratio and the immune microenvironment improve the prognostic prediction of pancreatic ductal adenocarcinoma. Discov Oncol 2023; 14:124. [PMID: 37405518 DOI: 10.1007/s12672-023-00744-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 06/29/2023] [Indexed: 07/06/2023] Open
Abstract
Tumor-infiltrating immune cells and fibroblasts are significant components of the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), and they participate in tumor progression as closely as tumor cells. However, the relationship between the features of the TME and patient outcomes and the interactions among TME components are still unclear. In this study, we evaluated the PDAC TME in terms of the quantity and location of cluster of differentiation (CD)4+ T cells, CD8+ T cells, macrophages, stromal maturity, and tumor-stroma ratio (TSR), as evaluated by immunohistochemical staining of serial whole-tissue sections from 116 patients with PDAC. The density of T cells and macrophages (mainly activated macrophages) was significantly higher at the invasive margins (IMs) than at the tumor center (TC). CD4+ T cells were significantly association with all the other tumor-associated immune cells (TAIs) including CD8, CD68 and CD206 positive cells. Tumors of the non-mature (intermediate and immature) stroma type harbored significantly more CD8+ T cells at the IMs and more CD68+ macrophages at the IMs and the TC. The density of CD4+, CD8+, and CD206+ cells at the TC; CD206+ cells at the IMs; and tumor-node-metastasis (TNM) staging were independent risk factors for patient outcomes, and the c-index of the risk nomogram for predicting the survival probability based on the TME features and TNM staging was 0.772 (95% confidence interval: 0.713-0.832). PDAC harbored a significantly immunosuppressive TME, of which the IMs were the hot zones for TAIs, while cells at the TC were more predictive of prognosis. Our results indicated that the model based on the features of the TME and TNM staging could predict patient outcomes.
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Affiliation(s)
- Mei Lu
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
- Fuqing City Hospital Affiliated to Fujian Medical University, Fuqing, Fujian, China
| | - Yi Zou
- Department of Pathology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Peiling Fu
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Yuyang Li
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Pengcheng Wang
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Guoping Li
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Sheng Luo
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Yupeng Chen
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Guoping Guan
- Fuqing City Hospital Affiliated to Fujian Medical University, Fuqing, Fujian, China
| | - Sheng Zhang
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Linying Chen
- Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
- Fujian Key Laboratory of Translational Research in Cancer and Nurodegernerative Diseases, Fuzhou, Fujian, China.
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Joshi VB, Gutierrez Ruiz OL, Razidlo GL. The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights. Cancers (Basel) 2023; 15:cancers15072169. [PMID: 37046830 PMCID: PMC10093482 DOI: 10.3390/cancers15072169] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes.
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Affiliation(s)
- Vidhu B Joshi
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Omar L Gutierrez Ruiz
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Gina L Razidlo
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
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Liu B, He S, Li C, Feng C, Wang H, Zhang H, Tu C, Li Z. Integration analysis based on fatty acid metabolism robustly predicts prognosis, dissecting immunity microenvironment and aiding immunotherapy for soft tissue sarcoma. Front Genet 2023; 14:1161791. [PMID: 37065471 PMCID: PMC10097927 DOI: 10.3389/fgene.2023.1161791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
Background: Soft tissue sarcoma (STS) is a highly malignant tumor with a dismal prognosis. Presently, the dysregulation of fatty acid metabolism has received increasing attention in tumor research, but fewer reports are relevant to STS.Methods: Based on fatty acid metabolism-related genes (FRGs), a novel risk score for STS was developed utilizing univariate analysis and least absolute shrinkage selection operator (LASSO) Cox regression analyses in the STS cohort, which were further validated using the external validation cohort from other databases. Furthermore, independent prognostic analysis, C-index, ROC curves, and nomogram were carried out to investigate the predictive performance of fatty acid-related risk scores. We also analysed the differences in enrichment pathways, the immune microenvironment, gene mutations, and immunotherapy response between the two distinct fatty acid score groups. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) was used to further verify the expression of FRGs in STS.Results: A total of 153 FRGs were retrieved in our study. Next, a novel fatty acid metabolism-related risk score (FAS) was constructed based on 18 FRGs. The predictive performance of FAS was also verified in external cohorts. In addition, the independent analysis, C-index, ROC curve, and nomograph also revealed that FAS could serve as an independent prognostic factor for the STS patients. Meanwhile, our results demonstrated that the STS cohort in two distinct FAS groups had different copy number variations, immune cell infiltration, and immunotherapy responses. Finally, the in vitro validation results demonstrated that several FRGs included in the FAS exhibited abnormal expression in STS.Conclusion: Altogether, our work comprehensively and systematically clarifies fatty acid metabolism’s potential roles and clinical significance in STS. The novel individualized score based on fatty acid metabolism may be provided as a potential marker and treatment strategy in STS.
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Affiliation(s)
- Binfeng Liu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shasha He
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chenbei Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chengyao Feng
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Haixia Zhang
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Chao Tu, ; Zhihong Li,
| | - Zhihong Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Chao Tu, ; Zhihong Li,
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Zhu YH, Zheng JH, Jia QY, Duan ZH, Yao HF, Yang J, Sun YW, Jiang SH, Liu DJ, Huo YM. Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol (Dordr) 2023; 46:17-48. [PMID: 36367669 DOI: 10.1007/s13402-022-00741-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.
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Affiliation(s)
- Yu-Heng Zhu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jia-Hao Zheng
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Qin-Yuan Jia
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Zong-Hao Duan
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Hong-Fei Yao
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jian Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Yong-Wei Sun
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 800 Dongchuan Road, 200240, People's Republic of China.
| | - De-Jun Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
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Li T, Chen D, Liu H, Tao Y, He X, Zang S, Li J, Zhang L, Li M, Liu J, He Q. Spatially targeting and regulating tumor-associated macrophages using a raspberry-like micellar system sensitizes pancreatic cancer chemoimmunotherapy. NANOSCALE 2022; 14:13098-13112. [PMID: 35972382 DOI: 10.1039/d2nr03053e] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Dense stroma and an immunosuppressive microenvironment severely hamper the antitumor therapeutic results of pancreatic cancer. Tumor-associated macrophages (TAMs) support the proliferation and invasion of tumor cells and contribute to the information of the immunosuppressive tumor microenvironment (TME). The repolarization of TAMs activates the antitumor immune response and sensitizes chemotherapy. Nevertheless, the difference in distributed mode between TAMs and tumor cells in tumor turns out to be an obstacle for dual targeting. To repolarize TAMs and elevate the chemoimmunotherapy outcome against pancreatic cancer, co-loading the TME responsive micellar system with gemcitabine (GEM) and PI3K inhibitor wortmannin (Wtmn) was used to dual target TAMs and tumor cells. GEM conjugated dendritic poly-lysine DGL (GD) nanoparticles were linked to polycaprolactone-polyethylene glycol micelles encapsulated with Wtmn (PP/Wtmn) via a cathepsin B (CTSB) substrate peptide to obtain raspberry-like GD@PP/Wtmn micelles. Upon arrival at the TME, GD was released in response to highly expressed CTSB, allowing deep penetration of the tumor and overcoming of the stromal barrier, while PP/Wtmn remained in the perivascular area where TAMs abundantly resided. By inhibiting the PI3K pathway, the M2-like TAMs were repolarized into M1-like TAMs and then activated antitumor immunity, further synergizing with GEM to suppress tumor growth. This tumor and TAMs dual targeting nanoplatform provides an alternative approach to sensitize chemoimmunotherapy against pancreatic cancer.
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Affiliation(s)
- Ting Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Dong Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Houqin Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Yuan Tao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Xuan He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Shuya Zang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Jiaxin Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Ling Zhang
- College of Polymer Science and Engineering, Sichuan university, Chengdu 610065, China
| | - Man Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
| | - Ji Liu
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
| | - Qin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
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11
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Checkpoints and Immunity in Cancers: Role of GNG12. Pharmacol Res 2022; 180:106242. [DOI: 10.1016/j.phrs.2022.106242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/24/2022]
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12
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Mohseni G, Li J, Ariston Gabriel AN, Du L, Wang YS, Wang C. The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer. Front Immunol 2021; 12:781032. [PMID: 34858438 PMCID: PMC8630697 DOI: 10.3389/fimmu.2021.781032] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/25/2021] [Indexed: 12/23/2022] Open
Abstract
The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.
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Affiliation(s)
- Ghazal Mohseni
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Abakundana Nsenga Ariston Gabriel
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun-Shan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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13
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Yang SH, Lu LC, Kao HF, Chen BB, Kuo TC, Kuo SH, Tien YW, Bai LY, Cheng AL, Yeh KH. Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma. Oncoimmunology 2021; 10:1973710. [PMID: 34595057 PMCID: PMC8477954 DOI: 10.1080/2162402x.2021.1973710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/09/2021] [Accepted: 08/24/2021] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy (n = 142) or FOLFIRINOX regimen (n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume.
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Affiliation(s)
- Shih-Hung Yang
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Li-Chun Lu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsiang-Fong Kao
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Bang-Bin Chen
- Department of Medical Imaging and Radiology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Li-Yuan Bai
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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14
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Eight-year longitudinal study of whole blood gene expression profiles in individuals undergoing long-term medical follow-up. Sci Rep 2021; 11:16564. [PMID: 34400700 PMCID: PMC8368195 DOI: 10.1038/s41598-021-96078-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/04/2021] [Indexed: 12/25/2022] Open
Abstract
Blood circulates throughout the body via the peripheral tissues, contributes to host homeostasis and maintains normal physiological functions, in addition to responding to lesions. Previously, we revealed that gene expression analysis of peripheral blood cells is a useful approach for assessing diseases such as diabetes mellitus and cancer because the altered gene expression profiles of peripheral blood cells can reflect the presence and state of diseases. However, no chronological assessment of whole gene expression profiles has been conducted. In the present study, we collected whole blood RNA from 61 individuals (average age at registration, 50 years) every 4 years for 8 years and analyzed gene expression profiles using a complementary DNA microarray to examine whether these profiles were stable or changed over time. We found that the genes with very stable expression were related mostly to immune system pathways, including antigen cell presentation and interferon-related signaling. Genes whose expression was altered over the 8-year study period were principally involved in cellular machinery pathways, including development, signal transduction, cell cycle, apoptosis, and survival. Thus, this chronological examination study showed that the gene expression profiles of whole blood can reveal unmanifested physiological changes.
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15
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Kiaie SH, Sanaei MJ, Heshmati M, Asadzadeh Z, Azimi I, Hadidi S, Jafari R, Baradaran B. Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development. Acta Pharm Sin B 2021; 11:1083-1097. [PMID: 34094821 PMCID: PMC8144893 DOI: 10.1016/j.apsb.2020.12.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/29/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Immunotherapy has been recently considered as a promising alternative for cancer treatment. Indeed, targeting of immune checkpoint (ICP) strategies have shown significant success in human malignancies. However, despite remarkable success of cancer immunotherapy in pancreatic cancer (PCa), many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far. In this process, immunosuppression in the tumor microenvironment (TME) is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method. In this paper, the latest findings on the ICPs, which mediate immunosuppression in the TME have been reviewed. In addition, different approaches for targeting ICPs in the TME of PCa have been discussed. This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.
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Affiliation(s)
- Seyed Hossein Kiaie
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
- Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
| | - Mohammad Javad Sanaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Masoud Heshmati
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
| | - Iman Azimi
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7001, Tasmania, Australia
| | - Saleh Hadidi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Reza Jafari
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia 5714783734, Iran
- Department of Immunology and Genetics, School of Medicine, Urmia University of Medical Sciences, Urmia 5714783734, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
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16
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Kumar S, Singh SK, Rana B, Rana A. Tumor-infiltrating CD8 + T cell antitumor efficacy and exhaustion: molecular insights. Drug Discov Today 2021; 26:951-967. [PMID: 33450394 PMCID: PMC8131230 DOI: 10.1016/j.drudis.2021.01.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 11/20/2020] [Accepted: 01/07/2021] [Indexed: 02/06/2023]
Abstract
Host immunity has an essential role in the clinical management of cancers. Therefore, it is advantageous to choose therapies that can promote tumor cell death and concurrently boost host immunity. The dynamic tumor microenvironment (TME) determines whether an antineoplastic drug will elicit favorable or disparaging immune responses from tumor-infiltrating lymphocytes (TILs). CD8+ T cells are one of the primary tumor-infiltrating immune cells that deliver antitumor responses. Here, we review the influence of various factors in the TME on CD8+ T cell exhaustion and survival, and possible strategies for restoring CD8+ T cell effector function through immunotherapy.
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Affiliation(s)
- Sandeep Kumar
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA.
| | - Sunil Kumar Singh
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA
| | - Basabi Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA
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17
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Javadrashid D, Baghbanzadeh A, Hemmat N, Hajiasgharzadeh K, Nourbakhsh NS, Lotfi Z, Baradaran B. Envisioning the immune system to determine its role in pancreatic ductal adenocarcinoma: Culprit or victim? Immunol Lett 2021; 232:48-59. [PMID: 33647329 DOI: 10.1016/j.imlet.2021.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC.
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Affiliation(s)
- Darya Javadrashid
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ziba Lotfi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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Bednarz-Misa I, Bromke MA, Krzystek-Korpacka M. Interleukin (IL)-7 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1290:9-49. [PMID: 33559853 DOI: 10.1007/978-3-030-55617-4_2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Interleukin (IL)-7 plays an important immunoregulatory role in different types of cells. Therefore, it attracts researcher's attention, but despite the fact, many aspects of its modulatory action, as well as other functionalities, are still poorly understood. The review summarizes current knowledge on the interleukin-7 and its signaling cascade in context of cancer development. Moreover, it provides a cancer-type focused description of the involvement of IL-7 in solid tumors, as well as hematological malignancies.The interleukin has been discovered as a growth factor crucial for the early lymphocyte development and supporting the growth of malignant cells in certain leukemias and lymphomas. Therefore, its targeting has been explored as a treatment modality in hematological malignancies, while the unique ability to expand lymphocyte populations selectively and without hyperinflammation has been used in experimental immunotherapies in patients with lymphopenia. Ever since the early research demonstrated a reduced growth of solid tumors in the presence of IL-7, the interleukin application in boosting up the anticancer immunity has been investigated. However, a growing body of evidence indicative of IL-7 upregulation in carcinomas, facilitating tumor growth and metastasis and aiding drug-resistance, is accumulating. It therefore becomes increasingly apparent that the response to the IL-7 stimulus strongly depends on cell type, their developmental stage, and microenvironmental context. The interleukin exerts its regulatory action mainly through phosphorylation events in JAK/STAT and PI3K/Akt pathways, while the significance of MAPK pathway seems to be limited to solid tumors. Given the unwavering interest in IL-7 application in immunotherapy, a better understanding of interleukin role, source in tumor microenvironment, and signaling pathways, as well as the identification of cells that are likely to respond should be a research priority.
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Affiliation(s)
- Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Mariusz A Bromke
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
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Luo Y, Hu J, Liu Y, Li L, Li Y, Sun B, Kong R. Invadopodia: A potential target for pancreatic cancer therapy. Crit Rev Oncol Hematol 2021; 159:103236. [PMID: 33482351 DOI: 10.1016/j.critrevonc.2021.103236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 01/05/2021] [Accepted: 01/16/2021] [Indexed: 02/08/2023] Open
Abstract
Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
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Affiliation(s)
- Yan Luo
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jisheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yong Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yilong Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Kong
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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20
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Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors. J Control Release 2020; 330:1095-1105. [PMID: 33188827 DOI: 10.1016/j.jconrel.2020.11.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 09/27/2020] [Accepted: 11/09/2020] [Indexed: 12/26/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, where even surgical resection and aggressive chemotherapy produce dismal outcomes. Immunotherapy is a promising alternative to conventional treatments, possessing the ability to elicit T cell-mediated killing of tumor cells and prevent disease recurrence. Immunotherapeutic approaches thus far have seen limited success in PDAC due to a poorly immunogenic and exceedingly immunosuppressive tumor microenvironment, which is enriched with dysfunctional and immunosuppressed antigen-presenting cells (APCs). We developed a highly potent immunostimulatory nanoparticle (immuno-NP) to activate and expand APCs in the tumor and induce local secretion of interferon β (IFNβ), which is a pro-inflammatory cytokine that plays a major role in APC recruitment. The effectiveness of the immuno-NP stems from its dual cargo of two synergistic immune modulators consisting of an agonist of the stimulator of interferon genes (STING) pathway and an agonist of the Toll-like receptor 4 (TLR4) pathway. We show the functional synergy of the dual-agonist cargo can be tweaked by adjusting the ratio of the two agonists loaded in the immuno-NP, leading to an increase in IFNβ production (11-fold) compared to any single agonist immuno-NP variant. Using the orthotopic murine Panc02 model of PDAC, we show that systemic administration allowed immuno-NPs to deposit into the perivascular regions of the tumor, which coincided with the APC-rich tumor areas leading to predominant uptake of immuno-NPs by APCs. The immuno-NPs were effectively taken up by a significant portion of dendritic cells in the tumor (>56%). This led to a significant expansion of APCs, resulting in an 11.5-fold increase of dendritic cells and infiltration of lymphocytes throughout the pancreatic tumor compared to untreated animals.
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Ho TTB, Nasti A, Seki A, Komura T, Inui H, Kozaka T, Kitamura Y, Shiba K, Yamashita T, Yamashita T, Mizukoshi E, Kawaguchi K, Wada T, Honda M, Kaneko S, Sakai Y. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis. J Immunother Cancer 2020; 8:e001367. [PMID: 33188035 PMCID: PMC7668383 DOI: 10.1136/jitc-2020-001367] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis. METHODS The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated. RESULTS In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages. CONCLUSION The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.
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Affiliation(s)
- Tuyen Thuy Bich Ho
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Alessandro Nasti
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Takuya Komura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Kanazawa, Japan
| | - Hiiro Inui
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takashi Kozaka
- Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Yoji Kitamura
- Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Kazuhiro Shiba
- Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
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Melzer MK, Arnold F, Stifter K, Zengerling F, Azoitei N, Seufferlein T, Bolenz C, Kleger A. An Immunological Glance on Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020; 21:ijms21093345. [PMID: 32397303 PMCID: PMC7246613 DOI: 10.3390/ijms21093345] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/23/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Different factors such as mutational landscape, intra- and intertumoral heterogeneity, stroma, and immune cells impact carcinogenesis of PDAC associated with an immunosuppressive microenvironment. Different cell types with partly opposing roles contribute to this milieu. In recent years, immunotherapeutic approaches, including checkpoint inhibitors, were favored to treat cancers, albeit not every cancer entity exhibited benefits in a similar way. Indeed, immunotherapies rendered little success in pancreatic cancer. In this review, we describe the communication between the immune system and pancreatic cancer cells and propose some rationale why immunotherapies may fail in the context of pancreatic cancer. Moreover, we delineate putative strategies to sensitize PDAC towards immunological therapeutics and highlight the potential of targeting neoantigens.
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Affiliation(s)
- Michael Karl Melzer
- Department of Urology, Ulm University Hospital, 89081 Ulm, Germany; (M.K.M.); (F.Z.); (C.B.)
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
| | - Frank Arnold
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
| | - Katja Stifter
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
| | - Friedemann Zengerling
- Department of Urology, Ulm University Hospital, 89081 Ulm, Germany; (M.K.M.); (F.Z.); (C.B.)
| | - Ninel Azoitei
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
| | - Thomas Seufferlein
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
| | - Christian Bolenz
- Department of Urology, Ulm University Hospital, 89081 Ulm, Germany; (M.K.M.); (F.Z.); (C.B.)
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (F.A.); (K.S.); (N.A.); (T.S.)
- Correspondence:
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Loft ND, Vaengebjerg S, Skov L. Cancer risk in patients with psoriasis: should we be paying more attention? Expert Rev Clin Immunol 2020; 16:479-492. [DOI: 10.1080/1744666x.2020.1754194] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Nikolai Dyrberg Loft
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Sofie Vaengebjerg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
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Liu X, Xu J, Zhang B, Liu J, Liang C, Meng Q, Hua J, Yu X, Shi S. The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications. Mol Cancer 2019; 18:184. [PMID: 31831007 PMCID: PMC6909567 DOI: 10.1186/s12943-019-1117-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/03/2019] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.
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Affiliation(s)
- Xiaomeng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
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Benzing C, Lam H, Tsang CM, Rimmer A, Arroyo-Berdugo Y, Calle Y, Wells CM. TIMP-2 secreted by monocyte-like cells is a potent suppressor of invadopodia formation in pancreatic cancer cells. BMC Cancer 2019; 19:1214. [PMID: 31836008 PMCID: PMC6911299 DOI: 10.1186/s12885-019-6429-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/03/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. METHODS To specifically test the impact of interaction on invasive potential two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia and invade in a spheroid invasion assay. RESULTS Interestingly when the PDAC cells were co-cultured with undifferentiated THP1 monocyte-like cells invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. CONCLUSIONS Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC.
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Affiliation(s)
- Christian Benzing
- School of Cancer and Pharmaceutical Sciences, New Hunts House, Kings College London, London, SE1 1UL, UK.,Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hoyin Lam
- School of Cancer and Pharmaceutical Sciences, New Hunts House, Kings College London, London, SE1 1UL, UK
| | - Chi Man Tsang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hongkong, Hong Kong SAR
| | - Alexander Rimmer
- School of Cancer and Pharmaceutical Sciences, New Hunts House, Kings College London, London, SE1 1UL, UK
| | | | - Yolanda Calle
- Department of Life Sciences, University of Roehampton, London, UK
| | - Claire M Wells
- School of Cancer and Pharmaceutical Sciences, New Hunts House, Kings College London, London, SE1 1UL, UK.
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Computational STAT3 activity inference reveals its roles in the pancreatic tumor microenvironment. Sci Rep 2019; 9:18257. [PMID: 31796877 PMCID: PMC6890662 DOI: 10.1038/s41598-019-54791-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/18/2019] [Indexed: 12/18/2022] Open
Abstract
Transcription factor (TF) STAT3 contributes to pancreatic cancer progression through its regulatory roles in both tumor cells and the tumor microenvironment (TME). In this study, we performed a systematic analysis of all TFs in patient-derived gene expression datasets and confirmed STAT3 as a critical regulator in the pancreatic TME. Importantly, we developed a novel framework that is based on TF target gene expression to distinguish between environmental- and tumor-specific STAT3 activities in gene expression studies. Using this framework, our results novelly showed that compartment-specific STAT3 activities, but not STAT3 mRNA, have prognostications towards clinical values within pancreatic cancer datasets. In addition, high TME-derived STAT3 activity correlates with an immunosuppressive TME in pancreatic cancer, characterized by CD4 T cell and monocyte infiltration and high copy number variation burden. Where environmental-STAT3 seemed to play a dominant role at primary pancreatic sites, tumor-specific STAT3 seemed dominant at metastatic sites where its high activity persisted. In conclusion, by combining compartment-specific inference with other tumor characteristics, including copy number variation and immune-related gene expression, we demonstrate our method’s utility as a tool to generate novel hypotheses about TFs in tumor biology.
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de la Fuente J, Sharma A, Chari S, Majumder S. Peripheral blood monocyte counts are elevated in the pre-diagnostic phase of pancreatic cancer: A population based study. Pancreatology 2019; 19:1043-1048. [PMID: 31630918 PMCID: PMC7897401 DOI: 10.1016/j.pan.2019.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes. A biomarker with incremental change in the pre-diagnostic phase of the disease would be valuable for early detection. In our clinical experience, we have observed elevated peripheral blood monocyte (PBM) counts in PDAC patients at diagnosis. In this study, we aimed to compare PBM counts in PDAC cases and healthy controls at diagnosis and in the 2-year pre-diagnostic period. METHODS Using the Rochester Epidemiology Project database, we identified all patients diagnosed with PDAC between 2000 and 2015 (n = 219) and age-and gender-matched disease-free controls (n = 438). PBM counts and temporal trends were analyzed over a 24 month period before PDAC diagnosis. The groups were compared using Fisher's exact test and t-test. RESULTS At diagnosis, compared to controls PDAC cases more often had monocytosis (23% vs 8%; p < 0.001) and higher mean PBM count (x109/L) (0.73 vs 0.59; p < 0.001). In the 2-year pre-diagnostic period, mean PBM counts were significantly higher in PDAC cases in the interval from 6 months to diagnosis (0.69 vs 0.61; p = 0.03). PDAC cases with monocytosis at diagnosis had a significantly lower median survival (1.9 months vs. 7.6 months; p = 0.001). CONCLUSION Monocytosis is more prevalent in PDAC patients at diagnosis compared to controls and is associated with lower median survival. In a subset of patients, PBM count elevation precedes PDAC diagnosis by 6 months. This novel observation can possibly augment strategies for early diagnosis of PDAC but needs further study.
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Affiliation(s)
- Jaime de la Fuente
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ayush Sharma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Suresh Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Shounak Majumder
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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An inflammatory subtype of pancreatic ductal adenocarcinoma is associated with poor prognosis and increased perioperative mortality. JOURNAL OF PANCREATOLOGY 2019. [DOI: 10.1097/jp9.0000000000000022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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Bednarz-Misa I, Diakowska D, Krzystek-Korpacka M. Local and Systemic IL-7 Concentration in Gastrointestinal-Tract Cancers. ACTA ACUST UNITED AC 2019; 55:medicina55060262. [PMID: 31185636 PMCID: PMC6630562 DOI: 10.3390/medicina55060262] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/17/2019] [Accepted: 06/05/2019] [Indexed: 12/26/2022]
Abstract
Background and objectives: Interleukin-7 (IL-7) is exploited in cancer immunotherapies although its status in solid tumors is largely unknown. We aimed to determine its systemic and local concentrations in esophageal (EC), gastric (GC), and colorectal (CRC) cancers. Materials and Methods: IL-7 was immunoenzymatically measured in paired surgical specimens of tumors and tumor-adjacent tissue (n = 48), and in the sera of 170 individuals (54 controls and 116 cancer patients). Results: IL-7 was higher in tumors as compared to noncancerous tissue in all cancers (mean difference: 29.5 pg/g). The expression ratio (tumor to normal) was 4.4-fold in GC, 2.2-fold in EC, and 1.7-fold in CRC. However, when absolute concentrations were compared, the highest IL-7 concentrations were in CRC, both when tumor and noncancerous tissue were analyzed. In CRC tumors, IL-7 was 2 and 1.5 times higher than in EC and GC tumors. In noncancerous CRC tissue, IL-7 was 2.3- and 2.8-fold higher than in EC and GC. IL-7 overexpression was more pronounced in Stage 3/4 and N1 cancers as a result of decreased cytokine expression in noncancerous tissue. Tumor location was a key factor in determining both local and systemic IL-7 concentrations. Serum IL-7 in CRC and EC was higher than in controls, GC, and patients with adenocarcinoma of gastric cardia (CC), but no significant correlation with the disease advancement could be observed. Conclusions: IL-7 protein is overexpressed in EC, GC, and CRC, but concentrations differ both in tumor and tumor-adjacent tissue with respect to tumor location. More advanced cancers have lower IL-7 concentrations in the immediate environment of the tumor. At the systemic level, IL-7 is elevated in CRC and EC, but not CC or GC. IL-7 dependence on the location of the primary tumor should be taken into account in future IL-7-based immunotherapies. Functional studies explaining a role of IL-7 in gastrointestinal cancers are needed.
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Affiliation(s)
- Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland.
| | - Dorota Diakowska
- Department of Gastrointestinal and General Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland.
- Department of Nervous System Diseases, Wroclaw Medical University, 51-618 Wroclaw, Poland.
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Fujinaga H, Sakai Y, Yamashita T, Arai K, Terashima T, Komura T, Seki A, Kawaguchi K, Nasti A, Yoshida K, Wada T, Yamamoto K, Kume K, Hasegawa T, Takata T, Honda M, Kaneko S. Biological characteristics of gene expression features in pancreatic cancer cells induced by proton and X-ray irradiation. Int J Radiat Biol 2019; 95:571-579. [PMID: 30557072 DOI: 10.1080/09553002.2019.1558297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Radiation therapy is an important alternative treatment for advanced cancer. The aim of the current study was to disclose distinct alterations of the biological characteristics of gene expression features in pancreatic cancer cells, MIAPaCa-2, following proton and X-ray irradiation. MATERIALS AND METHODS Using cDNA microarray, we examined the gene expression alterations of MIAPaCa-2 cells following proton or X-ray irradiation. We also isolated the surviving MIAPaCa-2 cells after irradiation and analyzed their gene expression profiles. RESULTS Although the cytocidal effects of both types of irradiation were similar at sufficient doses in vitro and in vivo, the affected gene expression profile alterations of MIAPaCa-2 cells irradiated with protons were distinct from those irradiated with X-ray. Interestingly, clustering analysis of gene expression of the surviving MIAPaCa-2 cells was also completely discernible between the two types of irradiation. However, a similar cytocidal effect was still observed in the proton- and X-ray-irradiated surviving cells after re-irradiation, commonly showing biological effects related to apoptosis and cell cycle processes. CONCLUSIONS Proton irradiation treatment for pancreatic cancer provides the distinct biological effect of steady gene expression alterations compared to X-ray irradiation; however, surviving cells from both types of irradiation were still susceptible to the cytocidal effects induced by proton re-irradiation treatment.
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Affiliation(s)
- Haruo Fujinaga
- a Disease control and homeostasis , Kanazawa University , Kanazawa , Japan
| | - Yoshio Sakai
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Tatsuya Yamashita
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Kuniaki Arai
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Takeshi Terashima
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Takuya Komura
- c System Biology , Kanazawa University , Kanazawa , Japan
| | - Akihiro Seki
- c System Biology , Kanazawa University , Kanazawa , Japan
| | - Kazunori Kawaguchi
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Alessandro Nasti
- a Disease control and homeostasis , Kanazawa University , Kanazawa , Japan
| | - Keiko Yoshida
- a Disease control and homeostasis , Kanazawa University , Kanazawa , Japan
| | - Takashi Wada
- d Department of Nephrology , Kanazawa University Hospital , Kanazawa , Japan
| | | | - Kyo Kume
- e The Wakasa Wan Energy Research Center , Tsuruga , Japan
| | | | - Takushi Takata
- e The Wakasa Wan Energy Research Center , Tsuruga , Japan
| | - Masao Honda
- b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan
| | - Shuichi Kaneko
- a Disease control and homeostasis , Kanazawa University , Kanazawa , Japan.,b Department of Gastroenterology , Kanazawa University Hospital , Kanazawa , Japan.,c System Biology , Kanazawa University , Kanazawa , Japan
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Abstract
Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.
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Affiliation(s)
- Hélène Salmon
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- INSERM U932, Institut Curie, Paris, France.
| | | | - Sacha Gnjatic
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Sakai Y, Honda M, Matsui S, Komori O, Murayama T, Fujiwara T, Mizuno M, Imai Y, Yoshimura K, Nasti A, Wada T, Iida N, Kitahara M, Horii R, Toshikatsu T, Nishikawa M, Okafuji H, Mizukoshi E, Yamashita T, Yamashita T, Arai K, Kitamura K, Kawaguchi K, Takatori H, Shimakami T, Terashima T, Hayashi T, Nio K, Kaneko S, Hokuriku Liver Study Group. Development of novel diagnostic system for pancreatic cancer, including early stages, measuring mRNA of whole blood cells. Cancer Sci 2019; 110:1364-1388. [PMID: 30742728 PMCID: PMC6447845 DOI: 10.1111/cas.13971] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/01/2019] [Accepted: 02/07/2019] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC.
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Affiliation(s)
- Yoshio Sakai
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Masao Honda
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Shigeyuki Matsui
- Department of BiostatisticsNagoya University Graduate School of MedicineNagoyaJapan
| | - Osamu Komori
- Department of Computer and Information ScienceSeikei UniversitySeikeiJapan
| | | | - Tadami Fujiwara
- Center for Advanced Medicine and Clinical ResearchNagoya University HospitalNagoyaJapan
| | - Masaaki Mizuno
- Center for Advanced Medicine and Clinical ResearchNagoya University HospitalNagoyaJapan
| | - Yasuhito Imai
- Innovative Clinical Research CenterKanazawa UniversityKanazawaJapan
| | | | | | - Takashi Wada
- Department of NephrologyKanazawa University HospitalKanazawaJapan
| | - Noriho Iida
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Masaaki Kitahara
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Rika Horii
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Tamai Toshikatsu
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | | | - Hirofumi Okafuji
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Eishiro Mizukoshi
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Tatsuya Yamashita
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Taro Yamashita
- Department of General MedicineKanazawa University HospitalKanazawaJapan
| | - Kuniaki Arai
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Kazuya Kitamura
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | | | - Hajime Takatori
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Tetsuro Shimakami
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Takeshi Terashima
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Tomoyuki Hayashi
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Kouki Nio
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Shuichi Kaneko
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
- System BiologyKanazawa UniversityKanazawaJapan
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Sakai Y, Miyazawa M, Komura T, Yamada T, Nasti A, Yoshida K, Takabatake H, Yamato M, Yamashita T, Yamashita T, Mizukoshi E, Okuzono M, Ho TTB, Kawaguchi K, Wada T, Honda M, Kaneko S. Distinct chemotherapy-associated anti-cancer immunity by myeloid cells inhibition in murine pancreatic cancer models. Cancer Sci 2019; 110:903-912. [PMID: 30657234 PMCID: PMC6398897 DOI: 10.1111/cas.13944] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 01/11/2019] [Accepted: 01/12/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti-tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr-1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr-1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon-gamma (IFN-γ) were higher in GEM-treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell-depleted PDAC mice treated with GEM showed biological processes related to anti-cancer immunity, such as natural killer cell-mediated cytotoxicity, type I IFN signaling, and co-stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti-cancer effect, and depletion of myeloid-lineage cells played an important role in enhancing anti-cancer immunity associated with GEM treatment.
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Affiliation(s)
- Yoshio Sakai
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Masaki Miyazawa
- Disease Control and HomeostasisCollege of Medical Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
| | - Takuya Komura
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | - Takeshi Yamada
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | - Alessandro Nasti
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | - Keiko Yoshida
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | - Hisashi Takabatake
- Disease Control and HomeostasisCollege of Medical Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
| | - Masatoshi Yamato
- Disease Control and HomeostasisCollege of Medical Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
| | - Taro Yamashita
- Department of General MedicineKanazawa University HospitalKanazawaJapan
| | - Tatsuya Yamashita
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Eishiro Mizukoshi
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Mai Okuzono
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | - Tuyen Thuy Bich Ho
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
| | | | - Takashi Wada
- Department of NephrologyKanazawa University HospitalKanazawaJapan
| | - Masao Honda
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
| | - Shuichi Kaneko
- Department of GastroenterologyKanazawa University HospitalKanazawaJapan
- Disease Control and HomeostasisCollege of Medical Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
- System BiologyGraduate School of Advanced Preventive Medical SciencesKanazawa UniversityKanazawaJapan
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34
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Saponara E, Visentin M, Baschieri F, Seleznik G, Martinelli P, Esposito I, Buschmann J, Chen R, Parrotta R, Borgeaud N, Bombardo M, Malagola E, Caflisch A, Farhan H, Graf R, Sonda S. Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas. J Pathol 2018; 246:352-365. [PMID: 30058725 DOI: 10.1002/path.5147] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 07/03/2018] [Accepted: 07/26/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which is the primary cause of pancreatic cancer mortality, is poorly responsive to currently available interventions. Identifying new targets that drive PDAC formation and progression is critical for developing alternative therapeutic strategies to treat this lethal malignancy. Using genetic and pharmacological approaches, we investigated in vivo and in vitro whether uptake of the monoamine serotonin [5-hydroxytryptamine (5-HT)] is required for PDAC development. We demonstrated that pancreatic acinar cells have the ability to readily take up 5-HT in a transport-mediated manner. 5-HT uptake promoted activation of the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for transdifferentiation of acinar cells into acinar-to-ductal metaplasia (ADM), a key determinant in PDAC development. Consistent with the central role played by Rac1 in ADM formation, inhibition of the 5-HT transporter Sert (Slc6a4) with fluoxetine reduced ADM formation both in vitro and in vivo in a cell-autonomous manner. In addition, fluoxetine treatment profoundly compromised the stromal reaction and affected the proliferation and lipid metabolism of malignant PDAC cells. We propose that Sert is a promising therapeutic target to counteract the early event of ADM, with the potential to stall the initiation and progression of pancreatic carcinogenesis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Enrica Saponara
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital of Zurich, Zurich, Switzerland
| | - Francesco Baschieri
- Institute Gustave Roussy, Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France
| | - Gitta Seleznik
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Paola Martinelli
- Institute for Cancer Research, Medical University, Wien, Austria
| | - Irene Esposito
- Institut für Pathologie, University Hospital of Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
| | - Johanna Buschmann
- Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Rong Chen
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Rossella Parrotta
- Laboratory of Molecular Oncology, Thorax und Lungen Tumor Zentrum, University Hospital of Zurich, Zurich, Switzerland
| | - Nathalie Borgeaud
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Marta Bombardo
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Ermanno Malagola
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Amedeo Caflisch
- Department of Biochemistry, University of Zurich, Zurich, Switzerland
| | - Hesso Farhan
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Rolf Graf
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland.,Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Sabrina Sonda
- Department of Visceral and Transplant Surgery, University Hospital of Zurich, Zurich, Switzerland.,Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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Shi B, Li Q, Ma X, Gao Q, Li L, Chu J. High expression of programmed cell death protein 1 on peripheral blood T-cell subsets is associated with poor prognosis in metastatic gastric cancer. Oncol Lett 2018; 16:4448-4454. [PMID: 30214579 PMCID: PMC6126159 DOI: 10.3892/ol.2018.9190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 05/24/2018] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoints in solid tumors serve important roles in metastasis. The present study was designed to explore the expression of programmed cell death protein 1 (PD-1) on peripheral blood T-cell subsets and its role in the clinicopathological features and prognosis of patients with metastatic gastric cancer. The expression of PD-1 in peripheral blood T-cell subsets was detected in 100 metastatic gastric cancer patients prior to the first line chemotherapy by flow cytometric analysis. The potential associaton between the peripheral blood T-cell subsets PD-1 level and the clinicopathological features of patients with metastatic gastric cancer and the clinical outcomes was analyzed. The percent of high PD-1 expressed cluster of differentiation (CD)3+, CD3+CD4+ and CD3+CD8+ T-cells was 20.4, 13.0 and 9.4%, respectively in patients with metastatic gastric cancer. The overall survival (OS) and progression-free survival (PFS) rate of the 100 patients with metastatic gastric cancer was 12.2 and 3.9 months, respectively. Kaplan-Meier curve with long-rank analysis indicated that patients with higher PD-1+/CD3+, PD-1+/CD3+CD4+ and PD-1+/CD3+CD8+ levels had a worse prognosis (all P<0.05). Univariate and multivariate analysis revealed that high PD-1+/CD3+ [hazard ratio (HR), 2.145; P=0.015], high PD-1+/CD3+CD4+ (HR, 1.866; P=0.034) and high PD-1+/CD3+CD8+ (HR, 1.817; P=0.033) level in peripheral blood were independent risk factors for predicting the survival time of patients with metastatic gastric cancer. High PD-1+/CD3+, high PD-1+/CD3+CD4+ and high PD-1+/CD3+CD8+ expression conferred a lower overall survival rate in patients with metastatic gastric cancer. These results suggest that high PD-1 expression on peripheral blood T-cell subsets may potentially be novel prognostic biomarker for metastatic gastric cancer.
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Affiliation(s)
- Bian Shi
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Qiujian Li
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Xuhui Ma
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Qilong Gao
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Lu Li
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Junfeng Chu
- Department of Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
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36
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Immune Condition of Colorectal Cancer Patients Featured by Serum Chemokines and Gene Expressions of CD4+ Cells in Blood. Can J Gastroenterol Hepatol 2018; 2018:7436205. [PMID: 29992127 PMCID: PMC6016223 DOI: 10.1155/2018/7436205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 04/20/2018] [Accepted: 05/09/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC), the most common malignancy worldwide, causes inflammation. We explored the inflammatory pathophysiology of CRC by assessing the peripheral blood parameters. METHODS The differences in gene expression profiles of whole blood cells and cell subpopulations between CRC patients and healthy controls were analyzed using DNA microarray. Serum cytokine/chemokine concentrations in CRC patients and healthy controls were measured via multiplex detection immunoassays. In addition, we explored correlations between the expression levels of certain genes of peripheral CD4+ cells and serum chemokine concentrations. RESULTS The gene expression profiles of peripheral CD4+ cells of CRC patients differed from those of healthy controls, but this was not true of CD8+ cells, CD14+ cells, CD15+ cells, or CD19+ cells. Serum IL-8 and eotaxin-1 levels were significantly elevated in CRC patients, and the levels substantially correlated with the expression levels of certain genes of CD4+ cells. Interestingly, the relationships between gene expression levels in peripheral CD4+ cells and serum IL-8 and eotaxin-1 levels resembled those of monocytes/macrophages, not T cells. CONCLUSIONS Serum IL-8 and eotaxin-1 concentrations increased and were associated with changes in the gene expression of peripheral CD4+ cells in CRC patients.
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Foucher ED, Ghigo C, Chouaib S, Galon J, Iovanna J, Olive D. Pancreatic Ductal Adenocarcinoma: A Strong Imbalance of Good and Bad Immunological Cops in the Tumor Microenvironment. Front Immunol 2018; 9:1044. [PMID: 29868007 PMCID: PMC5960705 DOI: 10.3389/fimmu.2018.01044] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increased toxicity. Novel therapies are urgently required to improve PDAC patient survival. New treatments in other cancers such as melanoma, non-small-cell lung cancer, and renal cancer have emerged, based on immunotherapy targeting the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 or programmed death 1 ligand. However, the first clinical trials using such immune checkpoint inhibitors in PDAC have had limited success. Resistance to immunotherapy in PDAC remains unclear but could be due to tissue components (cancer-associated fibroblasts, desmoplasia, hypoxia) and to the imbalance between immunosuppressive and effector immune populations in the tumor microenvironment. In this review, we analyzed the presence of “good and bad immunological cops” in PDAC and discussed the significance of changes in their balance.
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Affiliation(s)
- Etienne D Foucher
- Team Immunity and Cancer, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France
| | - Clément Ghigo
- Team Cellular Stress, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France
| | - Salem Chouaib
- INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par La Ligue Contre Le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.,Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Jérôme Galon
- Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France
| | - Juan Iovanna
- Team Cellular Stress, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France
| | - Daniel Olive
- Team Immunity and Cancer, CRCM, Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France
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Abstract
Background Recent statistical methods for next generation sequencing (NGS) data have been successfully applied to identifying rare genetic variants associated with certain diseases. However, most commonly used methods (e.g., burden tests and variance-component tests) rely on large sample sizes. Notwithstanding, due to its-still high cost, NGS data is generally restricted to small sample sizes, that cannot be analyzed by most existing methods. Methods In this work, we propose a new exact association test for sequencing data that does not require a large sample approximation, which is applicable to both common and rare variants. Our method, based on the Generalized Cochran-Mantel-Haenszel (GCMH) statistic, was applied to NGS datasets from intraductal papillary mucinous neoplasm (IPMN) patients. IPMN is a unique pancreatic cancer subtype that can turn into an invasive and hard-to-treat metastatic disease. Results Application of our method to IPMN data successfully identified susceptible genes associated with progression of IPMN to pancreatic cancer. Conclusions Our method is expected to identify disease-associated genetic variants more successfully, and corresponding signal pathways, improving our understanding of specific disease’s etiology and prognosis.
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Affiliation(s)
- Joowon Lee
- Department of Statistics, Seoul National University, Seoul, South Korea
| | - Seungyeoun Lee
- Department of Applied Statistics, Sejong University, Seoul, South Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Taesung Park
- Department of Statistics, Seoul National University, Seoul, South Korea.
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39
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RNA sequencing analyses reveal novel differentially expressed genes and pathways in pancreatic cancer. Oncotarget 2018; 8:42537-42547. [PMID: 28418924 PMCID: PMC5522086 DOI: 10.18632/oncotarget.16451] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 02/27/2017] [Indexed: 12/14/2022] Open
Abstract
Gene expression microarrays have identified many tumor markers and therapeutic targets for pancreatic ductal adenocarcinoma (PDAC). However, microarray profilings have limited sensitivity and are prone to cross-hybridization between homologous DNA fragments. Here, we perform a transcriptome analysis of paired tumor and adjacent benign pancreatic tissues from 10 patients who underwent resection for PDAC. We identify a total of 2736 differentially expressed genes (DEGs) with false discovery rate less than 0.05, including 1554 upregulated, 1182 downregulated, and 6 microRNAs (miR-614, miR-217, miR-27b, miR-4451, miR-3609, and miR-612). Overexpression of five DEGs, i.e. KRT16, HOXA10, CDX1, SI, and SERPINB5 in tumors is confirmed by RT-PCR in 20 additional tissues. Overexpression of KRT16 in PDAC is also verified on protein level. In addition, top canonical pathways such as granulocyte adhesion and diapedesis pathway have been identified. Our study represents a comprehensive characterization of the PDAC transcriptome and provides insight to the mechanisms of pancreatic carcinogenesis and potential biomarkers and novel therapeutic targets for pancreatic cancer.
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40
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Gao HL, Liu L, Qi ZH, Xu HX, Wang WQ, Wu CT, Zhang SR, Xu JZ, Ni QX, Yu XJ. The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis. Hepatobiliary Pancreat Dis Int 2018; 17:95-100. [PMID: 29576277 DOI: 10.1016/j.hbpd.2018.03.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 01/17/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC. DATA SOURCES Electronic search of the PubMed, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival (OS). RESULTS Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry (IHC) was higher than that measured by polymerase chain reaction (PCR) (P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS (HR = 2.34; 95% CI: 1.78-3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3-4 group was higher than that in the T1-2 group (OR = 0.37; P = 0.001). CONCLUSIONS High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.
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Affiliation(s)
- He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Zi-Hao Qi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Shi-Rong Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin-Zhi Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Quan-Xing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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Xi T, Zhang G. Integrated analysis of tumor differentiation genes in pancreatic adenocarcinoma. PLoS One 2018; 13:e0193427. [PMID: 29596435 PMCID: PMC5875763 DOI: 10.1371/journal.pone.0193427] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 02/09/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Tumor differentiation is an important process in the development of cancer. It is valuable to identify key differentiation related genes in the prognosis and therapy of pancreatic adenocarcinoma. METHODS The mRNA expression data were downloaded from the Cancer Genome Atlas database. Then, differentially expressed tumor differentiation related genes were identified. Additionally, Gene Ontology functional categories and Kyoto Encyclopedia of Genes and Genomes biochemical pathway was used to explore the function. In addition, receiver operating characteristic and survival analysis were carried out to assess the diagnosis and prognosis value. Finally, the electronic validation of selected tumor differentiation related genes was performed. RESULTS A total of 932 genes were identified. Among which, 8 genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA and SSTR1 were differentially expressed in all different tumor differentiation grades. Functional analysis revealed those genes between highly differentiated and other differentiation were remarkably enriched in pancreatic adenocarcinoma and cell cycle pathway. Finally, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, BCL2L1, E2F1 and RAC1 were associated with the survival time of pancreatic adenocarcinoma patient. Among these genes, JUB, ERLIN1, FAM110B, MCM2 and BCL2L1 also had a diagnosis value for pancreatic adenocarcinoma. Additionally, the expression trend of JUB, HMGA2 and MCM2 was increased along with the tumor differentiation grades. And the expression trend of FAM110B was decreased along with the tumor differentiation grades. The electronic validation result was consistent with the bioinformatics analysis. CONCLUSIONS 12 tumor differentiation related genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA, SSTR1, BCL2L1, E2F1, RAC1 and STAT1 played crucial roles in the differentiation of pancreatic adenocarcinoma.
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Affiliation(s)
- Ting Xi
- Department of Gastroenterology, First People’s Hospital of Liaocheng, Liaocheng, Shandong Province, China
- * E-mail:
| | - Guizhi Zhang
- Department of Gastroenterology, Second People’s Hospital of Liaocheng, Liaocheng, Shandong Province, China
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Prognostic significance of preoperative gamma-glutamyltransferase to lymphocyte ratio index in nonfunctional pancreatic neuroendocrine tumors after curative resection. Sci Rep 2017; 7:13372. [PMID: 29042631 PMCID: PMC5645308 DOI: 10.1038/s41598-017-13847-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 10/02/2017] [Indexed: 02/08/2023] Open
Abstract
Various inflammation-based prognostic scores have been associated with reduced survival in patients with nonfunctional pancreatic neuroendocrine tumor (NF-PNET). However, few studies have illuminated the relationship between the preoperative gamma-glutamyltransferase (GGT) to lymphocyte ratio index (GLRI) and the prognosis of NF-PNET. A retrospective review of 125 NF-PNET patients following curative resection was conducted. The cut-off values for the inflammation-based prognostic scores, including GLRI, were selected using receiver operating characteristic curve analysis. Univariate, multivariate and Kaplan-Meier analyses were used to calculate overall survival (OS) and disease-free survival (DFS). The optimal cut-off value for GLRI was 10.3. Multivariate analysis showed that GLRI was an independent predictor of OS (P = 0.001) and DFS (P = 0.007) for NF-PNET. Kaplan-Meier analysis also showed that preoperative GLRI had significant prognostic value in various subgroups of patients with NF-PNET. The discriminatory capability of GLRI was superior to that of other inflammation-based scores in OS prediction. Furthermore, the predictive range was expanded by incorporating GLRI into the conventional stratification systems, including AJCC staging and WHO classification. These results indicated that preoperative GLRI was an independent predictor for NF-PNET patients undergoing curative resection. The incorporation of GLRI into the existing conventional stratification systems resulted in improved predictive accuracy.
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Komura T, Takabatake H, Harada K, Yamato M, Miyazawa M, Yoshida K, Honda M, Wada T, Kitagawa H, Ohta T, Kaneko S, Sakai Y. Clinical features of cystatin A expression in patients with pancreatic ductal adenocarcinoma. Cancer Sci 2017; 108:2122-2129. [PMID: 28898495 PMCID: PMC5666027 DOI: 10.1111/cas.13396] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 08/21/2017] [Accepted: 08/24/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy known, with an extremely poor prognosis due to the lack of an efficient diagnostic scheme and no radical treatment option, except surgery. Therefore, understanding the pathophysiology of, and finding a novel biomarker to detect, PDAC should be prioritized. We observed an increase in mRNA expression of the cysteine protease inhibitor cystatin A (CSTA) in CD4+ T cells in peripheral blood cells of nine patients with PDAC, compared with the expression in seven healthy volunteers. Moreover, we confirmed significantly higher CSTA mRNA expression in a larger cohort of 41 patients with PDAC compared with that in 20 healthy volunteers. Correspondingly, the serum CSTA concentrations in 36 patients with PDAC were higher than those in 37 healthy volunteers, and this increase was correlated with PDAC clinical stage. Furthermore, the expression of CSTA and cathepsin B, which is a lysosomal cysteine protease inhibited by CSTA, was observed in tumor tissues and tumor‐infiltrating immune cells in 20 surgically resected PDAC tissues by immunohistochemical staining. Expression of CSTA was detected in some tumor tissues and many tumor‐infiltrating immune cells. Cathepsin B expression was also observed in most tumor tissues and tumor‐infiltrating immune cells. In conclusion, CSTA and its substrate cathepsin B are involved in PDAC‐related inflammation. The increment of CSTA expression in peripheral blood of patients with PDAC may have a potential role as a PDAC immunopathologic biomarker.
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Affiliation(s)
- Takuya Komura
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hisashi Takabatake
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.,Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Masatoshi Yamato
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masaki Miyazawa
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Keiko Yoshida
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Takashi Wada
- Department of Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Hirohisa Kitagawa
- Department of Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Tetsuo Ohta
- Department of Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.,Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.,Department of Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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Zhang Y, Zhu W, Zhang X, Qu Q, Zhang L. Expression and clinical significance of programmed death-1 on lymphocytes and programmed death ligand-1 on monocytes in the peripheral blood of patients with cervical cancer. Oncol Lett 2017; 14:7225-7231. [PMID: 29344157 PMCID: PMC5754902 DOI: 10.3892/ol.2017.7105] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 03/17/2017] [Indexed: 12/21/2022] Open
Abstract
The programmed death-1 (PD-1) signaling pathway serves a critical role in immune regulation and tolerance by suppressing the activation and proliferation of T cells. The aim of the present study was to investigate the effect of PD-1 and programmed death-ligand 1 (PD-L1) on the development of cervical carcinoma and cervical intraepithelial neoplasia (CIN). A total of 40 healthy controls (HC), 40 patients with CIN and 66 newly diagnosed cervical cancer patients were recruited. The expression level of PD-1 expression on peripheral cluster of differentiation (CD)4+ and CD8+ T cells and PD-L1 on monocytes was analyzed by flow cytometry. The expression level of soluble PD-L1 in serum was determined by an ELISA. The results of the present study demonstrated that the PD-1 expression level on CD4+ and CD8+ T cells was significantly increased in CIN and cervical cancer, compared with that in HC. In addition, the PD-1 expression level on CD4+ and CD8+ T cells was increased in cervical cancer, compared with that in CIN. However, the expression level of PDL-1 on CD14+ monocytes was increased in cancer and CIN, but limited in cancer and CIN. In addition, PD-1 expression on CD4+ T cells was positively associated with PD-1 expression on CD8+ T cells in cervical cancer (P<0.05). Further analyses revealed that the proportion of PD-1 on CD4+ and CD8+ T cells were positively associated with tumor stages. However, no difference in the degree of soluble PD-1 among cancer, CIN and HC cells was revealed. The results suggested that the PD-1 signaling pathway is involved in the development of CIN and cervical cancer.
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Affiliation(s)
- Ying Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Weipei Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Xueguang Zhang
- Research Institute of Immunology, Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Qiuxia Qu
- Research Institute of Immunology, Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Liyuan Zhang
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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Dai JJ, Jiang MJ, Wang XP, Tian L. Inflammation-Related Pancreatic Carcinogenesis: Mechanisms and Clinical Potentials in Advances. Pancreas 2017; 46:973-985. [PMID: 28796135 DOI: 10.1097/mpa.0000000000000886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Chronic inflammation has long been considered critical in pancreatic carcinogenesis, and recently studies showed that some anti-inflammatory agents such as aspirin could potentially be used to attenuate pancreatic carcinogenesis. Several inflammation-related critical transcription factors and pathways such as NF-κB (nuclear factor κ-light-chain enhancer of activated B cells) and reactive oxygen species have been confirmed to be involved in carcinogenesis. However, its underlying mechanisms are far from clear, which largely limits further development of potential anticarcinogenesis drugs. As a result, it is of great importance for us to better understand and gain a better perspective in inflammation-related pancreatic carcinogenesis. In this review, we systematically analyzed recent advances concerning inflammation-related pancreatic carcinogenesis and brought out the possible underlying mechanisms. Potential preventive and therapeutic strategies based on anti-inflammatory agents have also been further discussed.
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Affiliation(s)
- Juan-Juan Dai
- From the *Shanghai Key Laboratory of Pancreatic Diseases, †Institute of Translational Medicine, and ‡Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Shinko D, Diakos CI, Clarke SJ, Charles KA. Cancer-Related Systemic Inflammation: The Challenges and Therapeutic Opportunities for Personalized Medicine. Clin Pharmacol Ther 2017; 102:599-610. [PMID: 28699186 DOI: 10.1002/cpt.789] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 06/23/2017] [Accepted: 07/06/2017] [Indexed: 12/15/2022]
Abstract
Over the last decade there has been significant progress towards the development of personalized or "precision" medicine for many patients with cancer. However, there still remain subpopulations of cancer patients that do not possess a tumor mutation profile that is successfully targeted by the newer molecular anticancer drugs and further personalized approaches are needed. The presence of cancer-related systemic inflammation represents an underappreciated subpopulation of cancer patients needing personalized therapy. For ∼25% of all advanced cancer patients, regardless of histological subtype, the patients with systemic inflammation have significantly poorer response to chemotherapy and also shorter overall survival compared to those cancer patients without inflammation. The development of cancer-related systemic inflammation involves interactions between host and tumor cells that are potential new drug targets in cancer chemotherapy. In this review we discuss the challenges and clinical opportunities to develop new therapeutic strategies for this underappreciated drug target.
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Affiliation(s)
- Diana Shinko
- Discipline of Pharmacology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Connie I Diakos
- Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratories, Kolling Institute of Medical Research, St Leonards, NSW, Australia
| | - Stephen J Clarke
- Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratories, Kolling Institute of Medical Research, St Leonards, NSW, Australia
| | - Kellie A Charles
- Discipline of Pharmacology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
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Sakai Y, Takamura M, Seki A, Sunagozaka H, Terashima T, Komura T, Yamato M, Miyazawa M, Kawaguchi K, Nasti A, Mochida H, Usui S, Otani N, Ochiya T, Wada T, Honda M, Kaneko S. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell. Regen Ther 2017; 6:52-64. [PMID: 30271839 PMCID: PMC6134901 DOI: 10.1016/j.reth.2016.12.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/12/2016] [Accepted: 12/08/2016] [Indexed: 12/14/2022] Open
Abstract
Introduction Adipose tissue stromal cells contain a substantial number of mesenchymal stem cells. As such, their application to regeneration of miscellaneous impaired organs has attracted much attention. Methods We designed a clinical study to investigate freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell (ADRC) therapy for liver cirrhosis and conducted treatment in four cirrhotic patients. ADRCs were isolated from autologous subcutaneous adipose tissue obtained by the liposuction method, followed with use of the Celution system adipose tissue dissociation device. The primary endpoint is assessment of safety one month after treatment. We also characterized the obtained ADRCs. Results Two patients had type C cirrhosis, one had nonalcoholic steatohepatitis-cirrhosis, and one had type B cirrhosis. No serious adverse events were observed during the 1-month study period after freshly isolated ADRC infusion. Serum albumin concentrations were maintained or improved during this period as well as during the succeeding follow-up of approximately 1 year in two patients and 6 months in another patient. Liver regeneration-related factors, namely hepatocyte growth factor and interleukin-6, were elevated 1 day after ADRC treatment in all patients. The obtained freshly isolated ADRCs were expanded in culture and found to express mesenchymal stem cell markers. Gene expression profile analysis of ADRCs was shown to involve inflammatory features, suggesting that characteristics of the obtained ADRCs were related to immunomodulatory biological effects. Conclusion This clinical study treatment for liver cirrhosis using ADRCs was proven to be safely conductible, and can be further investigated in future for regeneration/repair of liver cirrhosis.
Clinical study of liver cirrhosis therapy using adipose tissue-derived stromal cells. Autologous adipose tissue-derived stromal/stem (regenerative) cells were administered via intrahepatic arterial transfusion into cirrhotic patients. The obtained adipose tissue-derived stromal cells were shown to contain mesenchymal stem cells.
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Affiliation(s)
- Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Japan.,Department of Laboratory Medicine, Kanazawa University, Japan
| | - Masayuki Takamura
- Department of Cardiology, Kanazawa University Hospital, Japan.,System Biology, Kanazawa University, Japan
| | | | - Hajime Sunagozaka
- Department of Gastroenterology, Kanazawa University Hospital, Japan.,System Biology, Kanazawa University, Japan
| | | | | | - Masatoshi Yamato
- Department of Gastroenterology, Kanazawa University Hospital, Japan.,System Biology, Kanazawa University, Japan
| | | | | | | | | | - Soichiro Usui
- Department of Cardiology, Kanazawa University Hospital, Japan.,System Biology, Kanazawa University, Japan
| | | | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Institute, Japan
| | - Takashi Wada
- Department of Laboratory Medicine, Kanazawa University, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Japan.,System Biology, Kanazawa University, Japan
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Johansson H, Andersson R, Bauden M, Hammes S, Holdenrieder S, Ansari D. Immune checkpoint therapy for pancreatic cancer. World J Gastroenterol 2016; 22:9457-9476. [PMID: 27920468 PMCID: PMC5116591 DOI: 10.3748/wjg.v22.i43.9457] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 09/18/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy. However, due to small sample sizes, major results are not yet identifiable. The present article provides a clinical overview of immune checkpoint inhibition in pancreatic cancer. PubMed, ClinicalTrials.gov and American Society of Clinical Oncology's meeting abstracts were systematically searched for relevant clinical studies. Four articles, five abstracts and 25 clinical trials were identified and analyzed in detail.
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Elevated systemic interleukin-7 in patients with colorectal cancer and individuals at high risk of cancer: association with lymph node involvement and tumor location in the right colon. Cancer Immunol Immunother 2016; 66:171-179. [PMID: 27866242 PMCID: PMC5281653 DOI: 10.1007/s00262-016-1933-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 11/14/2016] [Indexed: 12/14/2022]
Abstract
Interleukin (IL)-7 is a cytokine essential for protective immunity, and it is considered as a promising agent for cancer immunotherapy. Recent studies, however, appear to associate IL-7 with aggressiveness of solid tumors. The IL-7 has been less studied in colorectal cancer (CRC) and conditions associated with increased risk of CRC development. To explore IL-7 status in bowel diseases, it was measured immunofluorometrically in 431 individuals (110 with CRC) by using Luminex platform. A level of IL-7 in CRC patients was significantly higher than in controls, did not differ from those with adenomas, but was lower than in both active and inactive inflammatory bowel disease (IBD) cases. In CRC, IL-7 was higher in patients with lymph node and distant metastases and with tumors located in right colon. In adenomas, IL-7 elevation was associated exclusively with villous growth pattern, while in IBD, circulating IL-7 reflected clinical activity of Crohn’s disease and ulcerative colitis. Systemic TNFα, IL-10, and PDGF-BB were independent predictors of circulating IL-7. In summary, our study is the first to demonstrate IL-7 elevation in CRC in association with metastatic disease and tumor location. Both associations should be considered when designing IL-7-based immunotherapies for CRC. Further studies on IL-7 functionality in CRC are necessary.
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50
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Chiesa Fuxench ZC, Shin DB, Ogdie Beatty A, Gelfand JM. The Risk of Cancer in Patients With Psoriasis: A Population-Based Cohort Study in the Health Improvement Network. JAMA Dermatol 2016; 152:282-90. [PMID: 26676102 DOI: 10.1001/jamadermatol.2015.4847] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
IMPORTANCE The risk of cancer in patients with psoriasis remains a cause of special concern due to the chronic inflammatory nature of the disease, the use of immune-suppressive treatments and UV therapies, and the increased prevalence of comorbid, well-established risk factors for cancer, such as smoking and obesity, all of which may increase the risk of carcinogenesis. OBJECTIVE To compare the overall risk of cancer, and specific cancers of interest, in patients with psoriasis compared with patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of patients ages 18 to 89 years with no medical history of human immunodeficiency virus, cancer, organ transplants, or hereditary disease (albinism and xeroderma pigmentosum), prior to the start date, conducted using The Health Improvement Network, a primary care medical records database in the United Kingdom. The data analyzed had been collected prospectively from 2002 through January 2014. The analysis was completed in August 2015. EXPOSURES OF INTEREST Patients with at least 1 diagnostic code for psoriasis were classified as having moderate-to-severe disease if they had been prescribed psoralen, methotrexate, cyclosporine, acitretin, adalimumab, etanercept, infliximab, or ustekinumab or phototherapy for psoriasis. Patients were classified as having mild disease if they never received treatment with any of these agents. MAIN OUTCOMES AND MEASURES Incident cancer diagnosis. RESULTS A total of 937,716 control group patients without psoriasis, matched on date and practice visit, and 198,366 patients with psoriasis (186,076 with mild psoriasis and 12,290 with moderate-to-severe disease) were included in the analysis. The adjusted hazard ratios (aHRs) with 95% CIs for any incident cancer excluding nonmelanoma skin cancer (NMSC) were 1.06 (95% CI, 1.02-1.09), 1.06 (95% CI, 1.02-1.09), and 1.08 (95% CI, 0.96-1.22) in the overall, mild, and severe psoriasis group. The aHRs for incident lymphoma were 1.34 (95% CI, 1.18-1.51), 1.31 (95% CI, 1.15-1.49), and 1.89 (95% CI, 1.25-2.86); for NMSC, 1.12 (95% CI, 1.07-1.16), 1.09 (95% CI, 1.05-1.13), and 1.61 (95% CI, 1.42-1.84); and for lung cancer, 1.15 (95% CI, 1.03-1.27), 1.12 (95% CI, 1.01-1.25), and 1.62 (95% CI, 1.16-2.28) in the overall, mild, and severe psoriasis groups, respectively. No significant association was seen with cancer of the breast, colon, prostate, or leukemia. CONCLUSIONS AND RELEVANCE The association between psoriasis and cancer, albeit small, was present in our cohort of patients with psoriasis. This association was primarily driven by NMSC, lymphoma, and lung cancer.
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Affiliation(s)
- Zelma C Chiesa Fuxench
- Departments of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia2Epidemiology and Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Daniel B Shin
- Departments of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Alexis Ogdie Beatty
- Epidemiology and Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia3Department of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Joel M Gelfand
- Departments of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia2Epidemiology and Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia
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