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Tong L, Kremer V, Neo SY, Seitz C, Tobin NP, Seliger B, Harmenberg U, Colón E, Scherman Plogell AH, Liu LL, Lundqvist A. Cellular and secretome profiling uncover immunological biomarkers in the prognosis of renal cell carcinoma patients. Oncoimmunology 2025; 14:2481109. [PMID: 40126183 PMCID: PMC11934188 DOI: 10.1080/2162402x.2025.2481109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025] Open
Abstract
Renal cell carcinoma (RCC) is recognized as an immunogenic tumor, yet tumor-infiltrating lymphocytes often exhibit diminished effector function. However, the mechanisms underlying reduced T and NK cell activity in RCC remain unclear. Here, we examined the immune contexture in RCC patients undergoing nephrectomy to identify immune-related biomarkers associated with disease progression. Immune cell phenotypes and secretion profiles were assessed using flow cytometry and Luminex multiplex analysis. Supervised multivariate analysis revealed several changes of which frequencies of T and NK cells expressing CCR5, CXCR3, and PD-1 were elevated within tumors compared with peripheral blood. In addition, higher levels of regulatory T cells, PD-1+, and CXCR3+ T and NK cells were observed in patients with relapse following nephrectomy. With regards to soluble factors, tumor-derived CXCL8 was associated with higher Fuhrman grade and increased frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These biomarkers demonstrate potential relevance in the progression of RCC and merit further investigation in prospective studies.
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Affiliation(s)
- Le Tong
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Veronika Kremer
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Shi Yong Neo
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Republic of Singapore
| | - Christina Seitz
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Nicholas P. Tobin
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Barbara Seliger
- Institute for Medical Immunology, Martin-Luther University Halle-Wittenberg, Halle, Germany
- Institute of Translational Immunology, Medical School “Theodor Fontane”, Brandenburg an der Havel, Germany
| | - Ulrika Harmenberg
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Eugenia Colón
- Department of Women’s and Children’s Health, Karolinska Institutet and S:t Göran’s Hospital-Unilabs, Stockholm, Sweden
| | | | - Lisa L. Liu
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Andreas Lundqvist
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Zhang H, Li H, Qi Y, He J, Deng L, Chen S, Pan H, Guo H. IL17A/F secreted by ASCT2-overexpression ovarian cancer cells contributes to immune escape through the suppression of natural killer (NK) cells cytotoxicity by the activation of c-JUN/ PTGS2 pathway. Int Immunopharmacol 2025; 150:114226. [PMID: 39954656 DOI: 10.1016/j.intimp.2025.114226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/23/2025] [Accepted: 02/02/2025] [Indexed: 02/17/2025]
Abstract
Ovarian cancer (OC) is a deadly gynecologic cancer associated with metastasis, recurrence, and treatment resistance. The expression of the alanine-serine-cysteine transporter 2 (ASCT2) has been linked to poor prognosis and immune cell infiltration in OC tumors, but the underlying mechanisms are unclear. Lentiviral constructs were used to manipulate ASCT2 expression in OC cells (SKOV-3). The effects of ASCT2 on SKOV-3 behaviors including proliferation, invasion, migration, apoptosis, and cell cycle were assessed using various assays. The correlation between ASCT2 expression and immune infiltration in OC was analyzed using the Cancer Genome Atlas (TCGA) database. Co-culture experiments were conducted to evaluate the impact of ASCT2 overexpression in SKOV-3 on NK cells, followed by transcriptomics and cytokine analysis. ASCT2 expression and cytokine levels were characterized using qPCR and western blotting. ASCT2 overexpression significantly promoted cell proliferation, invasion, migration, and the percentage of G1-phase cells, while inhibiting apoptosis. ASCT2 silencing had the opposite effect. The expression of ASCT2 was negatively associated with NK cells in OC. ASCT2 overexpression in SKOV-3 cells led to excessive IL-17A/F production and inhibited the antitumor activity of NK cells, possibly through activating the IL-17 signaling pathway. The core regulatory genes c-JUN/PTGS2 in this pathway were upregulated, and antitumor cytokines were decreased in co-cultured NK cells, resulting in decreased antitumor activity and immune infiltration within the tumor. Our results suggest that overexpression of ASCT2 may play a predominant role in OC and NK cell immune infiltration within the tumor.
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Affiliation(s)
- Huixiang Zhang
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Library, Kunming Medical University, No.1168 West Chunrong Road, Chenggong District, Kunming, Yunnan 650500, China
| | - Haohan Li
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yanyan Qi
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Junhan He
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Langping Deng
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shipu Chen
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hong Pan
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Huiming Guo
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Xi W, Hou Y, Hou J, Guo J. Pseudocapsule thickness is positively associated with prognosis in patients with clear cell renal cell carcinoma. BMC Cancer 2025; 25:279. [PMID: 39962404 PMCID: PMC11834655 DOI: 10.1186/s12885-025-13721-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 02/12/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Tumour pseudocapsule shows plasticity, whose representative indicator- pseudocapsule thickness- was little studied in clear cell renal cell carcinoma (ccRCC). METHODS We enrolled 1037 ccRCC patients who underwent surgery between 2006 and 2013 at our institution. The patients did not receive therapy before surgery and were confirmed to have a pathological pseudocapsule. The associations of pseudocapsule thickness with overall survival and disease-free survival were studied using multivariable Cox regression analyses. Patients were stratified using points of maximum separation. Influential factors were examined with logistic regression. RESULTS The average thickness was 0.47 mm (median: 0.43, interquartile range: 0.28-0.6). The average follow-up was 92.1. In multivariable analyses, every 0.1-mm increase in thickness resulted in a decreased risk of death (hazard ratio (HR) 0.906, p = 0.011) but not recurrence (HR 0.948, p = 0.105). For patients with a pseudocapsule thickness of 0.2 mm, 0.4 mm, 0.6 mm, 0.8 mm and 1.0 mm, the estimated 10-year overall survival rates were 74.9%, 83.3%, 87.8%, 90.1% and 91.0%, and the 10-year disease-free survival rates were 69.6%, 76.6%, 80.8%, 83.1% and 84.1%, respectively, with the best cut-off value being approximately 0.37 mm. The results of logistic regression revealed that female sex (p < 0.001), age (p = 0.002), a higher neutrophil count (p = 0.011), large tumour size (p < 0.001) and necrosis (p = 0.011) were independently associated with a thin pseudocapsule (≤ 0.37 mm). CONCLUSIONS Pseudocapsule thickness is heterogeneous in clear cell renal cell carcinoma. Generally, increased thickness is associated with improvement in long-term survival. A pseudocapsule being 0.37 mm or thinner is mostly influenced by both systematic and tumor-related parameters.
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Affiliation(s)
- Wei Xi
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jianming Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Pedde AM, Kim H, Donakonda S, Baumann T, Bayerl F, Meiser P, Hirschberger A, Klement C, Grassmann S, Öllinger R, Hüser N, Hartmann D, Laschinger M, Trapani JA, Zippelius A, Bald T, Wiedemann GM, Rad R, Sun JC, Höchst B, Böttcher JP. Tissue-colonizing disseminated tumor cells secrete prostaglandin E2 to promote NK cell dysfunction and evade anti-metastatic immunity. Cell Rep 2024; 43:114855. [PMID: 39541209 DOI: 10.1016/j.celrep.2024.114855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 08/07/2024] [Accepted: 09/24/2024] [Indexed: 11/16/2024] Open
Abstract
Natural killer (NK) cells are critical for anti-metastatic immunity and can eliminate metastasizing tumor cells within circulation and sites of metastatic seeding. Here, we show that disseminated tumor cells (DTCs) colonizing the mouse lung secrete prostaglandin E2 (PGE2) to locally induce NK cell dysfunction, allowing outgrowing metastases to escape immune control and establish metastatic disease. Mechanistically, PGE2 signaling through its receptors EP2 and EP4 mediates NK cell dysfunction, which leads to reprogramming of NK cell gene expression and results in impaired production of anti-metastatic cytokines. In human cancer patients, the PGE2-EP2/EP4 axis is associated with NK cell dysfunction within distant organ metastases. Disabling EP2/EP4 signaling in NK cells prevents their dysfunction in DTC-colonized lungs and achieves effective NK cell-mediated control of metastatic disease. Our findings reveal a suppressive signaling axis exploited by metastasizing tumor cells to escape immune control in distant organs that could be targeted for metastatic cancer therapy.
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Affiliation(s)
- Anna-Marie Pedde
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Hyunu Kim
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sainitin Donakonda
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Tobias Baumann
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Felix Bayerl
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Philippa Meiser
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Anna Hirschberger
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Christine Klement
- Institute of Molecular Oncology and Functional Genomics, School of Medicine and Health, TUM, Munich, Germany
| | - Simon Grassmann
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rupert Öllinger
- Institute of Molecular Oncology and Functional Genomics, School of Medicine and Health, TUM, Munich, Germany
| | - Norbert Hüser
- Department of Surgery, School of Medicine and Health, TUM, Munich, Germany
| | - Daniel Hartmann
- Department of Surgery, School of Medicine and Health, TUM, Munich, Germany; Department of Surgery, University Clinic Tübingen, M3 Research Center, Tübingen, Germany
| | - Melanie Laschinger
- Department of Surgery, School of Medicine and Health, TUM, Munich, Germany
| | - Joseph A Trapani
- Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne, VIC, Australia
| | - Alfred Zippelius
- Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Tobias Bald
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
| | - Gabriela M Wiedemann
- Department of Internal Medicine II, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, School of Medicine and Health, TUM, Munich, Germany
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Bastian Höchst
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Jan P Böttcher
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
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Choi WS, Kwon H, Yi E, Lee H, Kim JM, Park HJ, Choi EJ, Choi ME, Sung YH, Won CH, Sung CO, Kim HS. HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400920. [PMID: 38828677 PMCID: PMC11304315 DOI: 10.1002/advs.202400920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/10/2024] [Indexed: 06/05/2024]
Abstract
Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.
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Affiliation(s)
- Woo Seon Choi
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Hyung‐Joon Kwon
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Eunbi Yi
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Haeun Lee
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Jung Min Kim
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Hyo Jin Park
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Eun Ji Choi
- Department of DermatologyAsan Institute for Life SciencesAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Myoung Eun Choi
- Department of DermatologyAsan Institute for Life SciencesAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Young Hoon Sung
- Department of Cell and Genetic EngineeringAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Chong Hyun Won
- Department of DermatologyAsan Institute for Life SciencesAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Chang Ohk Sung
- Department of PathologyAsan Medical Institute of Convergence Science and TechnologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Hun Sik Kim
- Department of MicrobiologyStem Cell Immunomodulation Research CenterAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
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Du Z, Xiao Y, Deng G, Song H, Xue Y, Song H. CD3+/CD4+ cells combined with myosteatosis predict the prognosis in patients who underwent gastric cancer surgery. J Cachexia Sarcopenia Muscle 2024; 15:1587-1600. [PMID: 38894548 PMCID: PMC11294046 DOI: 10.1002/jcsm.13517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND This study aimed to investigate the predictive capacity of lymphocyte subpopulations, sarcopenia and myosteatosis for clinical outcomes in patients who underwent gastric cancer surgery. Additionally, the prognostic significance of CD3+/CD4+ cells in conjunction with myosteatosis was explored. METHODS A cohort of 190 patients with gastric cancer who underwent surgery and received computed tomography scans between July 2016 and December 2017 at our institution was examined. Complete clinical information and peripheral lymphocyte subpopulations were available for all patients. A comprehensive array of statistical methodologies was employed to scrutinize variances in both clinical and pathological characteristics among patients, with the aim of identifying autonomous prognostic determinants requisite for the development of a nomogram. Subsequent assessment of the predictive efficacy of the nomogram was conducted via calibration curve analysis. RESULTS The study comprised a cohort of 190 participants, encompassing 126 males (66.32%) and 64 females (33.68%), with a mean age of 58.47 (±11.37) years. Patients were stratified into three groups based on CD3+/CD4+ cells and myosteatosis, with 24 in Group 1, 87 in Group 2 and 79 in Group 3. Notably, patients in the third group exhibited significantly shorter progression-free survival (PFS) (hazard ratio [HR] = 0.208, P < 0.001) and overall survival (OS) (HR = 0.193, P < 0.001). The subset of peripheral blood lymphocytes exhibited elevated levels of CD3+/CD4+ cells (HR = 2.485, P < 0.001) and heightened CD4+/CD8+ ratios (HR = 1.705, P = 0.038), whereas diminished CD19+ cell counts (HR = 0.210, P = 0.032) correlated with improved OS in patients. The individuals presenting with sarcopenia (HR = 4.089, P = 0.023) and myosteatosis (HR = 2.857, P < 0.001) displayed reduced OS. The multivariate Cox regression analysis showed that pathological tumour-node-metastasis stage, CD19+ cells, sarcopenia and CD3+/CD4+ cell-myosteatosis were identified as independent prognostic factors for PFS and OS in patients. The constructed nomograms for PFS and OS yielded C-index values of 0.839 (95% confidence interval [CI]: 0.798-0.880) and 0.836 (95% CI: 0.792-0.879), respectively. The calibration analysis demonstrated that the nomograms accurately predicted the 3- and 5-year survival rates of PFS and OS in patients. CONCLUSIONS Lymphocyte subsets, including CD3+/CD4+ cells, CD4+/CD8+ ratio and CD19+ cells, are indicative of clinical prognosis in gastric cancer surgery patients. Body composition parameters, such as sarcopenia and myosteatosis, are also associated with the patient's prognosis. The combination of CD3+/CD4+ cells with myosteatosis demonstrates enhanced prognostic value, enabling the identification of patients at high risk of post-operative metastasis and recurrence.
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Affiliation(s)
- Zhongze Du
- Department of Gastrointestinal SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinHeilongjiangChina
| | - Youming Xiao
- Department of Pediatric SurgeryYaAn People's HospitalYa'anSichuanChina
| | - Guiming Deng
- Department of Gastrointestinal SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinHeilongjiangChina
| | - Haibin Song
- Department of Gastrointestinal SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinHeilongjiangChina
| | - Yingwei Xue
- Department of Gastrointestinal SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinHeilongjiangChina
| | - Hongjiang Song
- Department of Gastrointestinal SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinHeilongjiangChina
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Hong Z, Chen X, Wang L, Zhou X, He H, Zou G, Liu Q, Wang Y. ROCK2-RNA interaction map reveals multiple biological mechanisms underlying tumor progression in renal cell carcinoma. Hum Cell 2023; 36:1790-1803. [PMID: 37418232 DOI: 10.1007/s13577-023-00947-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 06/24/2023] [Indexed: 07/08/2023]
Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. Despite new therapeutic modalities, the outcomes for RCC patients remain unsatisfactory. Rho-associated coiled-coil forming protein kinase 2 (ROCK2) has previously been shown to be upregulated in RCC, and its expression was negatively correlated with patient survival. However, the precise molecular function of ROCK2 has remained unclear. Herein, using RNA-seq analysis of ROCK2 knockdown and control cells, we identified 464 differentially expressed genes, and 1287 alternative splicing events in 786-O RCC cells. Furthermore, mapping of iRIP-seq reads in 786-O cells showed a biased distribution at 5' UTR, intronic and intergenic regions. By comparing ROCK2-regulated alternative splicing and iRIP-seq data, we found 292 overlapping genes that are enriched in multiple tumorigenic pathways. Taken together, our work defined a complex ROCK2-RNA interaction map on a genomic scale in a human RCC cell line, which deepens our understanding of the molecular function of ROCK2 in cancer development.
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Affiliation(s)
- Zhengdong Hong
- Department of Urology Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuexin Chen
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China
| | - Lei Wang
- School of Pharmacy, Nanchang Medical College, Nanchang, China
- Jiangxi Health Vocational College, Nanchang, China
| | - Xiaocheng Zhou
- Department of Urology Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Haowei He
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China
| | - Gaode Zou
- Department of Urology Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qingnan Liu
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Yiqian Wang
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China.
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Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol 2023; 12:70. [PMID: 37563648 PMCID: PMC10413722 DOI: 10.1186/s40164-023-00431-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023] Open
Abstract
Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.
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Affiliation(s)
- Yalan Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Weilin Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Jiangping Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Department of Head and Neck Oncology and Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Jinrong Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Hematology Research Laboratory, Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Wei Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China.
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9
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Cheng Y, Kou W, Zhu Y. Preoperative Inflammation-Associated Blood Cell Markers in Patients with Non-Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Study. Int J Gen Med 2023; 16:3067-3080. [PMID: 37489129 PMCID: PMC10363385 DOI: 10.2147/ijgm.s417948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023] Open
Abstract
Purpose This study aimed to investigate the association between preoperative inflammation-associated blood cell markers and the prognosis of patients with non-metastatic clear cell renal cell carcinoma (ccRCC) who underwent nephrectomy. Patients and Methods We retrospectively analyzed data from our single-center cohort of patients who underwent radical or partial nephrectomy for non-metastatic ccRCC. The optimal cutoff values for red blood cell distribution width (RDW), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR) were determined using X-tile software. We evaluated recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) using the Kaplann-Meier method. Cox proportional-hazards regression models were utilized to assess predictors of RFS, CSS, and OS. The predictive accuracy was evaluated using Harrell's Concordance Index (C-index). Results A total of 444 patients who underwent nephrectomy were included in the study. The optimal cutoff values for RDW, PLR, NLR, and LMR were determined as 13.1, 157.3, 3.4, and 2.7, respectively. On univariate Cox regression analysis, NLR, PLR, and LMR were significant predictors for RFS, CSS, and OS. After adjusting for important prognostic factors, only NLR remained a significant prognostic marker for both CSS and OS. When NLR was added to the stage, size, grade, and necrosis (SSIGN) model, the C-index increased from 0.777 to 0.826 for CSS and from 0.703 to 0.734 for OS. Similarly, when NLR was added to the University of California, Los Angeles, Integrated Staging System (UISS), the C-index increased from 0.796 to 0.811 for CSS and from 0.735 to 0.745 for OS. Conclusion NLR is a reliable prognostic biomarker for patients with non-metastatic ccRCC. The prognostic capabilities of UISS and SSIGN models could be improved by adding NLR to UISS and SSIGN models.
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Affiliation(s)
- Yuling Cheng
- Department of Urology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China
| | - Wei Kou
- Department of Urology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China
| | - Yu Zhu
- Department of Urology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China
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10
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Shin E, Bak SH, Park T, Kim JW, Yoon SR, Jung H, Noh JY. Understanding NK cell biology for harnessing NK cell therapies: targeting cancer and beyond. Front Immunol 2023; 14:1192907. [PMID: 37539051 PMCID: PMC10395517 DOI: 10.3389/fimmu.2023.1192907] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/30/2023] [Indexed: 08/05/2023] Open
Abstract
Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain hematologic malignancies. However, there are several limitations that need to be addressed to target more cancer types. Natural killer (NK) cells are a type of innate immune cells that represent a unique biology in cancer immune surveillance. In particular, NK cells obtained from heathy donors can serve as a source for genetically engineered immune cell therapies. Therefore, NK-based therapies, including NK cells, CAR-NK cells, and antibodies that induce antibody-dependent cellular cytotoxicity of NK cells, have emerged. With recent advances in genetic engineering and cell biology techniques, NK cell-based therapies have become promising approaches for a wide range of cancers, viral infections, and senescence. This review provides a brief overview of NK cell characteristics and summarizes diseases that could benefit from NK-based therapies. In addition, we discuss recent preclinical and clinical investigations on the use of adoptive NK cell transfer and agents that can modulate NK cell activity.
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Affiliation(s)
- Eunju Shin
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea
| | - Seong Ho Bak
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Taeho Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Jin Woo Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
| | - Suk-Ran Yoon
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Haiyoung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Ji-Yoon Noh
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
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11
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Li C, Zhu M, Wang J, Wu H, Liu Y, Huang D. Role of m6A modification in immune microenvironment of digestive system tumors. Biomed Pharmacother 2023; 164:114953. [PMID: 37269812 DOI: 10.1016/j.biopha.2023.114953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/21/2023] [Accepted: 05/27/2023] [Indexed: 06/05/2023] Open
Abstract
Digestive system tumors are huge health problem worldwide, largely attributable to poor dietary choices. The role of RNA modifications in cancer development is an emerging field of research. RNA modifications are associated with the growth and development of various immune cells, which, in turn, regulate the immune response. The majority of RNA modifications are methylation modifications, and the most common type is the N6-methyladenosine (m6A) modification. Here, we reviewed the molecular mechanism of m6A in the immune cells and the role of m6A in the digestive system tumors. However, further studies are required to better understand the role of RNA methylation in human cancers for designing diagnostic and treatment strategies and predicting the prognosis of patients.
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Affiliation(s)
- Chao Li
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Mengqi Zhu
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Jiajia Wang
- Department of Health Management, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Hengshuang Wu
- Department of Gynecological Pelvis Floor Reconstruction Ward, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Yameng Liu
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China.
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Kadono Y, Konaka H, Nohara T, Izumi K, Anai S, Fujimoto K, Koguchi T, Ishibashi K, Kawai N, Nakane K, Iba A, Masumori N, Takahara S, Mizokami A. Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study. Cancers (Basel) 2023; 15:2745. [PMID: 37345082 DOI: 10.3390/cancers15102745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/25/2023] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. METHODS This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. RESULTS Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. CONCLUSIONS There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.
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Affiliation(s)
- Yoshifumi Kadono
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Hiroyuki Konaka
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
- Department of Urology, Japanese Red Cross Society Kanazawa Hospital, Kanazawa 921-8162, Japan
| | - Takahiro Nohara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Kouji Izumi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Satoshi Anai
- Department of Urology, Nara Medical University, Kashihara 634-8522, Japan
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University, Kashihara 634-8522, Japan
| | - Tomoyuki Koguchi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Kei Ishibashi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Ishibashi Urology Clinic, Koriyama 963-8002, Japan
| | - Noriyasu Kawai
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Keita Nakane
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akinori Iba
- Department of Urology, Wakayama Medical University, Wakayama 641-8509, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Shizuko Takahara
- Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, Kanazawa 920-8641, Japan
| | - Atsushi Mizokami
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
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13
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Yu Y. The Function of NK Cells in Tumor Metastasis and NK Cell-Based Immunotherapy. Cancers (Basel) 2023; 15:cancers15082323. [PMID: 37190251 DOI: 10.3390/cancers15082323] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/09/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Metastatic tumors cause the most deaths in cancer patients. Treating metastasis remains the primary goal of current cancer research. Although the immune system prevents and kills the tumor cells, the function of the immune system in metastatic cancer has been unappreciated for decades because tumors are able to develop complex signaling pathways to suppress immune responses, leading them to escape detection and elimination. Studies showed NK cell-based therapies have many advantages and promise for fighting metastatic cancers. We here review the function of the immune system in tumor progression, specifically focusing on the ability of NK cells in antimetastasis, how metastatic tumors escape the NK cell attack, as well as the recent development of effective antimetastatic immunotherapies.
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Affiliation(s)
- Yanlin Yu
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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14
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Kruk L, Mamtimin M, Braun A, Anders HJ, Andrassy J, Gudermann T, Mammadova-Bach E. Inflammatory Networks in Renal Cell Carcinoma. Cancers (Basel) 2023; 15:cancers15082212. [PMID: 37190141 DOI: 10.3390/cancers15082212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Cancer-associated inflammation has been established as a hallmark feature of almost all solid cancers. Tumor-extrinsic and intrinsic signaling pathways regulate the process of cancer-associated inflammation. Tumor-extrinsic inflammation is triggered by many factors, including infection, obesity, autoimmune disorders, and exposure to toxic and radioactive substances. Intrinsic inflammation can be induced by genomic mutation, genome instability and epigenetic remodeling in cancer cells that promote immunosuppressive traits, inducing the recruitment and activation of inflammatory immune cells. In RCC, many cancer cell-intrinsic alterations are assembled, upregulating inflammatory pathways, which enhance chemokine release and neoantigen expression. Furthermore, immune cells activate the endothelium and induce metabolic shifts, thereby amplifying both the paracrine and autocrine inflammatory loops to promote RCC tumor growth and progression. Together with tumor-extrinsic inflammatory factors, tumor-intrinsic signaling pathways trigger a Janus-faced tumor microenvironment, thereby simultaneously promoting or inhibiting tumor growth. For therapeutic success, it is important to understand the pathomechanisms of cancer-associated inflammation, which promote cancer progression. In this review, we describe the molecular mechanisms of cancer-associated inflammation that influence cancer and immune cell functions, thereby increasing tumor malignancy and anti-cancer resistance. We also discuss the potential of anti-inflammatory treatments, which may provide clinical benefits in RCCs and possible avenues for therapy and future research.
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Affiliation(s)
- Linus Kruk
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Medina Mamtimin
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Attila Braun
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Joachim Andrassy
- Division of General, Visceral, Vascular and Transplant Surgery, Hospital of LMU, 81377 Munich, Germany
| | - Thomas Gudermann
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- German Center for Lung Research (DZL), 80336 Munich, Germany
| | - Elmina Mammadova-Bach
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
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15
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Guglietta S, Krieg C. Phenotypic and functional heterogeneity of monocytes in health and cancer in the era of high dimensional technologies. Blood Rev 2023; 58:101012. [PMID: 36114066 DOI: 10.1016/j.blre.2022.101012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022]
Abstract
Monocytes have been traditionally classified in three discrete subsets, which can participate in the immune responses as effector cells or as precursors of myeloid-derived cells in circulation and tissues. However, recent advances in single-cell omics have revealed unprecedented phenotypic and functional heterogeneity that goes well beyond the three conventional monocytic subsets and propose a more fluid differentiation model. This novel concept does not only apply to the monocytes in circulation but also at the tissue site. Consequently, the binary model proposed for differentiating monocyte into M1 and M2 macrophages has been recently challenged by a spectrum model that more realistically mirrors the heterogeneous cues in inflammatory conditions. This review describes the latest results on the high dimensional characterization of monocytes and monocyte-derived myeloid cells in steady state and cancer. We discuss how environmental cues and monocyte-intrinsic properties may affect their differentiation toward specific functional and phenotypic subsets, the causes of monocyte expansion and reduction in cancer, their metabolic requirements, and the potential effect on tumor immunity.
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Affiliation(s)
- Silvia Guglietta
- Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina (MUSC), 173 Ashley Avenue, CRI609, Charleston, SC 29425, USA.
| | - Carsten Krieg
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina (MUSC), 68 President Street, BE415, Charleston, SC 29425, USA; Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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16
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Lopes N, Vivier E, Narni-Mancinelli E. Natural killer cells and type 1 innate lymphoid cells in cancer. Semin Immunol 2023; 66:101709. [PMID: 36621291 DOI: 10.1016/j.smim.2022.101709] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 01/09/2023]
Abstract
Innate lymphoid cells (ILCs) are a group of innate lymphocytes that do not express RAG-dependent rearranged antigen-specific cell surface receptors. ILCs are classified into five groups according to their developmental trajectory and cytokine production profile. They encompass NK cells, which are cytotoxic, helper-like ILCs 1-3, which functionally mirror CD4+ T helper (Th) type 1, Th2 and Th17 cells respectively, and lymphoid tissue inducer (LTi) cells. NK cell development depends on Eomes (eomesodermin), whereas the ILC1 program is regulated principally by the transcription factor T-bet (T-box transcription factor Tbx21), that of ILC2 is regulated by GATA3 (GATA-binding protein 3) and that of ILC3 is regulated by RORγt (RAR-related orphan receptor γ). NK cells were discovered close to fifty years ago, but ILC1s were first described only about fifteen years ago. Within the ILC family, NK and ILC1s share many similarities, as witnessed by their cell surface phenotype which largely overlap. NK cells and ILC1s have been reported to respond to tissue inflammation and intracellular pathogens. Several studies have reported an antitumorigenic role for NK cells in both humans and mice, but data for ILC1s are both scarce and contradictory. In this review, we will first describe the different NK cell and ILC1 subsets, their effector functions and development. We will then discuss their role in cancer and the effects of the tumor microenvironment on their metabolism.
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Affiliation(s)
- Noella Lopes
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Eric Vivier
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France; Innate Pharma Research Laboratories, Innate Pharma, Marseille, France; APHM, Hôpital de la Timone, Marseille-Immunopôle, Marseille, France
| | - Emilie Narni-Mancinelli
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
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17
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Deng X, Terunuma H. Harnessing NK Cells to Control Metastasis. Vaccines (Basel) 2022; 10:vaccines10122018. [PMID: 36560427 PMCID: PMC9781233 DOI: 10.3390/vaccines10122018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
In recent years, tumor immunotherapy has produced remarkable results in tumor treatment. Nevertheless, its effects are severely limited in patients with low or absent pre-existing T cell immunity. Accordingly, metastasis remains the major cause of tumor-associated death. On the other hand, natural killer (NK) cells have the unique ability to recognize and rapidly act against tumor cells and surveil tumor cell dissemination. The role of NK cells in metastasis prevention is undisputable as an increase in the number of these cells mostly leads to a favorable prognosis. Hence, it is reasonable to consider that successful metastasis involves evasion of NK-cell-mediated immunosurveillance. Therefore, harnessing NK cells to control metastasis is promising. Circulating tumor cells (CTCs) are the seeds for distant metastasis, and the number of CTCs detected in the blood of patients with tumor is associated with a worse prognosis, whereas NK cells can eliminate highly motile CTCs especially in the blood. Here, we review the role of NK cells during metastasis, particularly the specific interactions of NK cells with CTCs, which may provide essential clues on how to harness the power of NK cells against tumor metastasis. As a result, a new way to prevent or treat metastatic tumor may be developed.
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Affiliation(s)
- Xuewen Deng
- Biotherapy Institute of Japan Inc., 2-4-8 Edagawa, Koto-ku, Tokyo 135-0051, Japan
- Correspondence: ; Tel.: +81-3-5632-6080; Fax: +81-3-5632-6083
| | - Hiroshi Terunuma
- Biotherapy Institute of Japan Inc., 2-4-8 Edagawa, Koto-ku, Tokyo 135-0051, Japan
- N2 Clinic Yotsuya, 5F 2-6 Samon-cho, Shinjuku-ku, Tokyo 160-0017, Japan
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Zhou J, Lin HP, Xu X, Wang XH, Rong L, Zhang Y, Shen L, Xu L, Qin WT, Ye Q, Ma XM, Bai YR. The predictive value of peripheral blood cells and lymphocyte subsets in oesophageal squamous cell cancer patients with neoadjuvant chemoradiotherapy. Front Immunol 2022; 13:1041126. [PMID: 36451825 PMCID: PMC9701713 DOI: 10.3389/fimmu.2022.1041126] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/27/2022] [Indexed: 02/11/2024] Open
Abstract
PURPOSE Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT. METHOD A total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates. RESULTS The numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT (P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased (P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR. CONCLUSION Lymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer.
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Affiliation(s)
- Jin Zhou
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hai-Ping Lin
- Department of Thoracic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Xu
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Hang Wang
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ling Rong
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yao Zhang
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Shen
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Xu
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Ting Qin
- Department of Thoracic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Ye
- Department of Thoracic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiu-Mei Ma
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong-Rui Bai
- Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Abstract
Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.
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Affiliation(s)
- Tamara J Laskowski
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander Biederstädt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
- Department of Medicine III: Hematology and Oncology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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20
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Alchahin AM, Mei S, Tsea I, Hirz T, Kfoury Y, Dahl D, Wu CL, Subtelny AO, Wu S, Scadden DT, Shin JH, Saylor PJ, Sykes DB, Kharchenko PV, Baryawno N. A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma. Nat Commun 2022; 13:5747. [PMID: 36180422 PMCID: PMC9525645 DOI: 10.1038/s41467-022-33375-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults. When ccRCC is localized to the kidney, surgical resection or ablation of the tumor is often curative. However, in the metastatic setting, ccRCC remains a highly lethal disease. Here we use fresh patient samples that include treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. Single-cell transcriptomic analysis of tumor cells from the primary tumors reveals a distinct transcriptional signature that is predictive of metastatic potential and patient survival. Analysis of supporting stromal cells within the tumor environment demonstrates vascular remodeling within the endothelial cells. An in silico cell-to-cell interaction analysis highlights the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Our findings provide biological insights into the interplay between tumor cells and the ccRCC microenvironment.
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Affiliation(s)
- Adele M Alchahin
- Childhood Cancer Research unit, Department of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Shenglin Mei
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
| | - Ioanna Tsea
- Childhood Cancer Research unit, Department of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Taghreed Hirz
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Youmna Kfoury
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Douglas Dahl
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chin-Lee Wu
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander O Subtelny
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Shulin Wu
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David T Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - John H Shin
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Philip J Saylor
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - David B Sykes
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Peter V Kharchenko
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Altos Labs, San Diego, CA, USA.
| | - Ninib Baryawno
- Childhood Cancer Research unit, Department of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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21
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Yang C, Yu T, Lin Q. A signature based on chromatin regulation and tumor microenvironment infiltration in clear cell renal cell carcinoma. Epigenomics 2022; 14:995-1013. [PMID: 36154213 DOI: 10.2217/epi-2022-0202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: This research aimed to construct a signature based on chromatin regulation in localized clear cell renal cell carcinoma (ccRCC). Materials & methods: Non-negative matrix factorization clustering was performed on 438 localized ccRCC cases. The immune infiltration was generated by the single-sample gene set enrichment analysis algorithm. Survival analyses were performed using the Kaplan-Meier method, and the significance of the differences was determined using the log-rank test. The risk score was constructed based on the expression of chromatin regulators to quantify chromatin modification. Results: A score system based on chromatin modification was established. The high-risk subtype was characterized by increased tumor mutation burden, whereas a low-risk score was characterized by an increase in chromatin regulator expression and better overall survival. Conclusion: This research has constructed a signature based on chromatin regulation in localized ccRCC.
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Affiliation(s)
- Chen Yang
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361003, China
| | - Tian Yu
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.,Department of General Surgery, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China
| | - Qin Lin
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361003, China
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22
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FXYD3 Expression Predicts Poor Prognosis in Renal Cell Carcinoma with Immunosuppressive Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14153596. [PMID: 35892856 PMCID: PMC9330147 DOI: 10.3390/cancers14153596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/15/2022] [Accepted: 07/17/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary FXYD3 belongs to the protein-coding gene family associated with Na+/K+-ATPase enzymes and chloride ion channels. Recently, the biological role of FXYD3 has been reported in multiple cancers. Nevertheless, the prognostic value of FXYD3 expression has been undiscovered in clear renal cell carcinoma (KIRC). In this study, we assessed the datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE29609). We found the FXYD3 high KIRC patients had distinct clinical characteristics, including hypoxia and poor overall survival. Furthermore, the algorithms discovered that FXYD3 mRNA levels were associated with tumor purity, multiple types of the tumor infiltrating lymphocytes (TILs) and several genes related to T cell exhaustion. In conclusion, FXYD3 predicts a poor prognosis associated with hypoxia, pro-tumor TILs, and T cell exhaustion in KIRC. Abstract FXYD3 is a protein-coding gene, belonging to the FXYD protein family associated with Na+/K+-ATPase enzymes and chloride ion channels. Accumulating evidence suggests the biological role of FXYD3 in multiple cancers. However, the prognostic value of FXYD3 expression in clear renal cell carcinoma (KIRC) is unclear. Therefore, we evaluated the clinical data with tumor-infiltrating lymphocytes (TILs) and immunoinhibitory gene expression data using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE29609). First, the FXYD3 high KIRC patients had distinct clinical characteristics, including age, sex, disease stage, histological grade, and hypoxia-related gene expressions. Next, FXYD3 gene expression was correlated with poor overall survival in both TCGA and GSE29609 cohorts. The ESTIMATE algorithm revealed that higher FXYD3 mRNA levels were associated with increased infiltration of immune cells and tumor purity. Moreover, the FXYD3 high KIRC tissue harbored increased TILs such as B cells, CD8+ T cells, and M1 macrophage, whereas NK cells and neutrophils were decreased. In addition, we showed FXYD3 was co-expressed with several immunoinhibitory genes related to T cell exhaustion such as LGALS9, CTLA4, BTLA, PDCD1, and LAG3. In conclusion, FXYD3 is an unfavorable prognostic biomarker associated with hypoxia, pro-tumor TILs, and T cell exhaustion.
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23
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Schietroma M, Romano L, Schiavi D, Pessia B, Mattei A, Fiasca F, Carlei F, Giuliani A. Systemic inflammation response index (SIRI) as predictor of anastomotic leakage after total gastrectomy for gastric cancer. Surg Oncol 2022; 43:101791. [DOI: 10.1016/j.suronc.2022.101791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 02/07/2023]
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24
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Wang R, Fu Y, Yao M, Cui X, Zhao Y, Lu X, Li Y, Lin Y, He S. The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin. FEBS J 2022; 289:6400-6419. [PMID: 35596723 DOI: 10.1111/febs.16531] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/21/2022] [Accepted: 05/19/2022] [Indexed: 11/26/2022]
Abstract
Hematological and neurological expressed 1 (HN1) is closely associated with the proliferation and metastasis of various tumors. However, the physiological functions and clinical significance of HN1 in hepatocellular carcinoma (HCC) remain indistinct. In this study, we investigated the role of HN1 in the pathogenesis of HCC and the underlying mechanism using clinical data from HCC patients, in vitro experiments utilizing HCC cell lines and in vivo animal models. We demonstrated that the overexpressed HN1 in HCC was correlated with patients' adverse outcomes. The gain and loss of function experiments indicated that HN1 could promote the proliferation, migration, and invasion of HCC cells in vitro. Furthermore, we found that HN1 knockdown sensitized HCC cells to oxaliplatin. Mechanically, HN1 prevented HMGB1 protein from ubiquitination and degradation via the autophagy-lysosome pathway, which was related to the interaction between HN1 protein and TRIM28 protein. In the nucleus, the downregulation of HMGB1 followed by HN1 knockdown resulted in increased DNA damage and cell death in the oxaliplatin-treated HCC cells. In the cytoplasm, HN1 regulated autophagy via HMGB1. Furthermore, HN1 knockdown in combination with HMGB1 overexpression restored the aggressive phenotypes of HCC cells and the sensitivity of these cells to oxaliplatin. HN1 knockdown inhibited the tumor growth and metastasis, and promoted the anticancer efficiency of oxaliplatin in vivo. In conclusion, our data suggest that the HN1/HMGB1 axis plays an important role in the development/progression and chemotherapy of HCC. Our findings indicate that the HN1/HMGB1 axis may be a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Ruhua Wang
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yunong Fu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Menglin Yao
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Xiaomeng Cui
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yan Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Xinlan Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yarui Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yiguang Lin
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Shuixiang He
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, China
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25
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Bonetti E, Jenzer M, Nientiedt C, Kaczorowski A, Geisler C, Zschäbitz S, Jäger D, Hohenfellner M, Duensing S, Reimold P. Interleukin-2 and Interferon-α for Advanced Renal Cell Carcinoma: Patient Outcomes, Sexual Dimorphism of Responses, and Multimodal Treatment Approaches over a 30-Year Period. Urol Int 2022; 106:1158-1167. [PMID: 35477131 DOI: 10.1159/000524097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/06/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Cytokine-based immunotherapy (IT) has been the mainstay of systemic treatment of advanced renal cell carcinoma (RCC) from the late 1980s until 2007. With the introduction of immune checkpoint inhibitors, a renaissance of immune oncological approaches is rapidly unfolding. MATERIALS AND METHODS In the present study, we revisited survival outcomes, sexual dimorphism of treatment responses, and the relevance of multimodal treatment approaches over a 30-year period in 156 patients with advanced RCC treated with subcutaneous (s.c.) interleukin-2 (IL-2) and interferon-α (IFN-α) between 1990 and 2009. RESULTS The median progression-free survival following the first IT was 5.8 months with a wide range from 0 to 197 months. The median overall survival (OS) was 25.8 months and the median cancer-specific survival after tumor nephrectomy was 24.6 months. A group of 29 patients (18.6%) and 11 patients (7.1%) survived longer than 5 and 10 years after surgery, respectively. A difference in the 5-year OS rate between male and female patients was detected (men, 21.6%; women, 11.1%). However, no sex-specific survival advantage was observed after 10 years. CONCLUSIONS We provide evidence that IT with s.c. IL-2 and IFN-α played a vital role in long-term survivors either by inducing lasting complete remissions or as part of multimodal approaches that allowed patients to survive until novel therapies became available. The implications for current immune oncological treatment approaches are being discussed.
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Affiliation(s)
- Eva Bonetti
- Department of Urology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Maximilian Jenzer
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Cathleen Nientiedt
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Adam Kaczorowski
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christine Geisler
- Department of Urology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Stefanie Zschäbitz
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Markus Hohenfellner
- Department of Urology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Duensing
- Department of Urology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.,Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Philipp Reimold
- Department of Urology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
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26
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Contribution of immature granulocyte level to diagnosis in pleural effusion. TURKISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2022; 30:257-263. [PMID: 36168576 PMCID: PMC9473606 DOI: 10.5606/tgkdc.dergisi.2022.21523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/18/2021] [Indexed: 12/03/2022]
Abstract
Background
In this study, we aimed to evaluate the diagnostic value of neutrophil and immature granulocyte levels in peripheral blood in cases with pleural effusion.
Methods
Between May 2019 and May 2020, a total of 117 patients (43 males, 74 females; mean age: 63.1±18.1 years; range, 18 to 93 years) who had pleural effusion and analysis of pleural fluid were retrospectively analyzed. All patients were evaluated in terms of age, sex, presence of comorbid diseases, approach to the pleural fluid, biochemical values of peripheral blood and pleural fluid, hemogram series of peripheral blood, diagnosis of pleural fluid, and mortality.
Results
Of the patients, 66 (54.5%) were diagnosed with benign pleural effusion and 51 (43.5%) were diagnosed with malignant pleural effusion. Number of cases with known primary malignancy was 54 (46.1%). Immature granulocyte count number and percentage of venous blood in the malignant pleural effusion group was significantly higher than the group with benign pleural effusion (p<0.05).
Conclusion
As a hemogram parameter, immature granulocyte level is an easily applicable, cheap, and a non-invasive method in the outpatient settings.
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27
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Sia J, Neeson PJ, Haynes NM. Basic cancer immunology for radiation oncologists. J Med Imaging Radiat Oncol 2022; 66:508-518. [PMID: 35352493 PMCID: PMC9311072 DOI: 10.1111/1754-9485.13406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/07/2022] [Accepted: 03/15/2022] [Indexed: 12/17/2022]
Abstract
Although the impressive clinical responses seen with modern cancer immunotherapy are currently limited to a subset of patients, the underlying paradigm shift has resulted in now hardly a segment in oncology that has not been touched by the immuno‐oncology revolution. A growing body of data indicates that radiation therapy (RT) can modulate the tumour immune microenvironment and complement cancer immunotherapy via non‐overlapping mechanisms to reinvigorate immunity against cancer. Thus, increasingly RT is viewed as a highly unique partner for immunotherapy across the spectrum of cancer settings, as radiobiology and cancer immunology foreseeably become more intertwined. Considering these developments, this review summarises the key concepts and terminology in immunology for the radiation oncologist, with a focus on the cancer setting and with reference to important recent advances. These concepts will provide a starting point for understanding the strategies that underlie current and emerging immunotherapy trials, as well as the indirect effects of RT by which immune responses against cancer are shaped.
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Affiliation(s)
- Joseph Sia
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Paul J Neeson
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Nicole M Haynes
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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28
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Abstract
Natural killer (NK) cells are innate immune cells that are critical to the body's antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.
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Affiliation(s)
- Isaac S. Chan
- Department of Internal Medicine, Division of Hematology and Oncology, and
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Andrew J. Ewald
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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29
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Lee MH, Järvinen P, Nísen H, Brück O, Ilander M, Uski I, Theodoropoulos J, Kankainen M, Mirtti T, Mustjoki S, Kreutzman A. T and NK cell abundance defines two distinct subgroups of renal cell carcinoma. Oncoimmunology 2022; 11:1993042. [PMID: 35003893 PMCID: PMC8741293 DOI: 10.1080/2162402x.2021.1993042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Renal cell carcinoma (RCC) is considered as an immunogenic cancer. Because not all patients respond to current immunotherapies, we aimed to investigate the immunological heterogeneity of RCC tumors. We analyzedthe immunophenotype of the circulating, tumor, and matching adjacent healthy kidney immune cells from 52 nephrectomy patients with multi-parameter flow cytometry. Additionally, we studied the transcriptomic and mutation profiles of 20 clear cell RCC (ccRCC) tumors with bulk RNA sequencing and a customized pan-cancer gene panel. The tumor samples clustered into two distinct subgroups defined by the abundance of intratumoral CD3+ T cells (CD3high, 25/52) and NK cells (NKhigh, 27/52). CD3high tumors had an overall higher frequency of tumor infiltrating lymphocytes and PD-1 expression on the CD8+ T cells compared to NKhigh tumors. The tumor infiltrating T and NK cells had significantly elevated expression levels of LAG-3, PD-1, and HLA-DR compared to the circulating immune cells. Transcriptomic analysis revealed increased immune signaling (IFN-γ, TNF-α via NF-κB, and T cell receptor signaling) and kidney metabolism pathways in the CD3high subgroup. Genomic analysis confirmed the typical ccRCC mutation profile including VHL, PBRM1, and SETD2 mutations, and revealed PBRM1 as a uniquely mutated gene in the CD3high subgroup. Approximately half of the RCC tumors have a high infiltration of NK cells associated with a lower number of tumor infiltrating lymphocytes, lower PD-1 expression, a distinct transcriptomic and mutation profile, providing insights to the immunological heterogeneity of RCC which may impact treatment responses to immunological therapies.
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Affiliation(s)
- Moon Hee Lee
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Petrus Järvinen
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Harry Nísen
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Oscar Brück
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Mette Ilander
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Ilona Uski
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Jason Theodoropoulos
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Matti Kankainen
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tuomas Mirtti
- Department of Pathology, Helsinki University Hospital and Research Program in Systems Oncology, University of Helsinki, Finland
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anna Kreutzman
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.,Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
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30
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Liu Q, You B, Meng J, Huang CP, Dong G, Wang R, Chou F, Gao S, Chang C, Yeh S, Xu W. Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling. Cancer Gene Ther 2022; 29:1988-2000. [PMID: 35915245 PMCID: PMC9750871 DOI: 10.1038/s41417-022-00506-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/18/2022] [Accepted: 07/06/2022] [Indexed: 01/25/2023]
Abstract
Although androgen receptor (AR) can influence bladder cancer (BCa) initiation and progression, its impact on tumor immune escape remains unclear. Here, we found that targeting AR could enhance natural killer (NK) cell tumor-killing efficacy by decreasing PD-L1 expression. Both antiandrogen treatment and AR knockdown effectively reduced membrane PD-LI expression to facilitate NK cell-mediated BCa cell killing by downregulating circ_0001005. Mechanistically, AR upregulated circRNA circ_0001005 expression via the RNA-editing gene ADAR2. circ_0001005 competitively sponged the miRNA miR-200a-3p to promote PD-L1 expression. A preclinical BCa xenograft mouse model further confirmed this newly identified signaling using the small molecule circ_0001005-shRNA to improve NK cell killing of BCa tumor cells. Collectively, these results suggest that targeting the newly identified ADAR2/circ_0001005/miR-200a-3p/PD-L1 pathway to impact antitumor immunity may suppress progression and boost immunotherapeutic efficacy in BCa.
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Affiliation(s)
- Qing Liu
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Bosen You
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Jialin Meng
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Chi-Ping Huang
- grid.411508.90000 0004 0572 9415Department of Urology, China Medical University/Hospital, Taichung, 404 Taiwan
| | - Guanglu Dong
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Ronghao Wang
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Fuju Chou
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Shan Gao
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Chawnshang Chang
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA ,grid.411508.90000 0004 0572 9415Department of Urology, China Medical University/Hospital, Taichung, 404 Taiwan
| | - Shuyuan Yeh
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Wanhai Xu
- grid.410736.70000 0001 2204 9268Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
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Salzano G, Perri F, Maglitto F, Togo G, De Fazio GR, Apolito M, Calabria F, Laface C, Vaira LA, Committeri U, Balia M, Pavone E, Aversa C, Salzano FA, Abbate V, Ottaiano A, Cascella M, Santorsola M, Fusco R, Califano L, Ionna F. Pre-Treatment Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Occult Cervical Metastasis in Clinically Negative Neck Supraglottic and Glottic Cancer. J Pers Med 2021; 11:1252. [PMID: 34945723 PMCID: PMC8706672 DOI: 10.3390/jpm11121252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 11/30/2022] Open
Abstract
Background. Among patients with diagnosis of Laryngeal Squamous Cell Carcinoma (LSCC), up to 37.5% of cases may have occult metastasis (OM), and this feature is linked to poor prognosis and high rate of local recurrence. The role of elective neck dissection (END) in clinically negative neck (cN0) LSCC remains controversial. It is of great value to search for low-cost and easily detectable indicators to predict the risk of OM in laryngeal cancer. Recent reports have shown that high values of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) represent a negative prognostic factor in head and neck cancers. The aim of our study has been to investigate the value of pre-treatment NLR and PLR with regard to predicting occult cervical metastasis in cN0 supraglottic and glottic LSCC. Materials and methods. Data of patients affected by LSCC, who had been surgically treated by means of laryngectomy (total, horizontal partial and supracricoid) and END between January 2006 and January 2021, were retrospectively reviewed, using information retrieved from a database dedicated to such procedures in a single tertiary care referral institute. Results. A total of 387 patients were treated for LSCC at our Institute from 2006 to 2021, but only 108 of them met the inclusion criteria. The median age at the time of diagnosis was 64 years (range, 39-89 years). All the tumors were treated with a laryngectomy and an END. A total of 27.7% of patients were found positive for neck node metastasis (the pN+ group), while 78/108 (72.3%) patients were found to be negative for the presence of neck metastasis (the pN0 group). High values of NLR, but not PLR, significantly correlated with the probability of OM, and according to the iterative algorithm of Newton-Raphson, an NLR value of 2.26 corresponds to a probability of OM of 20%. Conclusion. Our analysis revealed a statistical correlation between high NLR pre-treatment values and positive neck OM in patients with LSCC.
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Affiliation(s)
- Giovanni Salzano
- Maxillo-Facial and ENT Surgery Unit, INT-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (G.S.); (U.C.); (E.P.); (C.A.); (F.I.)
| | - Francesco Perri
- Head and Neck Medical and Experimental Oncology Unit, INT IRCCS Fondazione Giovanni Pascale, 80131 Naples, Italy
| | - Fabio Maglitto
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Giulia Togo
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Gianluca Renato De Fazio
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Michela Apolito
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Federica Calabria
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Claudia Laface
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Luigi Angelo Vaira
- Maxillofacial Surgery Unit, University Hospital of Sassari, 07100 Sassari, Italy;
| | - Umberto Committeri
- Maxillo-Facial and ENT Surgery Unit, INT-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (G.S.); (U.C.); (E.P.); (C.A.); (F.I.)
| | - Mario Balia
- Maxillofacial Surgery Unit, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy;
| | - Ettore Pavone
- Maxillo-Facial and ENT Surgery Unit, INT-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (G.S.); (U.C.); (E.P.); (C.A.); (F.I.)
| | - Corrado Aversa
- Maxillo-Facial and ENT Surgery Unit, INT-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (G.S.); (U.C.); (E.P.); (C.A.); (F.I.)
| | - Francesco Antonio Salzano
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy;
| | - Vincenzo Abbate
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Alessandro Ottaiano
- SSD Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (M.S.)
| | - Marco Cascella
- Division of Anesthesia, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy;
| | - Mariachiara Santorsola
- SSD Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (M.S.)
| | - Roberta Fusco
- Oncology Medical Division, Igea SpA, 80127 Naples, Italy;
| | - Luigi Califano
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy; (F.M.); (G.T.); (G.R.D.F.); (M.A.); (F.C.); (C.L.); (V.A.); (L.C.)
| | - Franco Ionna
- Maxillo-Facial and ENT Surgery Unit, INT-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (G.S.); (U.C.); (E.P.); (C.A.); (F.I.)
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Yin H, Wang X, Jin N, Ling X, Leng X, Wang Y, Ma K, Jiang X, Zhu J, Ma J. Integrated analysis of immune infiltration in esophageal carcinoma as prognostic biomarkers. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1697. [PMID: 34988206 PMCID: PMC8667131 DOI: 10.21037/atm-21-5881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/19/2021] [Indexed: 12/01/2022]
Abstract
Background Esophageal cancer (EC) is one of the most aggressive and lethal malignancies in the world. The quantity and distribution of immune cells are very important factors in determining cancer. Tumor-infiltrating mast cells (TIM) are a class of immune cells with an important immune regulation function for tumor progression. However, tumor-infiltrating immune cells (TIICs) and their role in EC have not yet been investigated. Methods The RNA-seq data of an EC cohort were downloaded from The Cancer Genome Atlas (TCGA) website. In this study, we used the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm to compare different soakage of inflammatory cells in esophageal squamous cell carcinoma (ESCC) and normal tissue. Kaplan-Meier survival analysis was performed on different immune cell subpopulations and overall survival (OS) in 22 human immune cell phenotypes. Immunohistochemistry (IHC) was also carried out using our clinical tissue samples. Results The proportion of tumor-infiltrating mast cells (TIM) significantly increased at the late of EC and a high percentage of mast cells indicated a poor OS of EC patients in TCGA database. The IHC staining of tryptase revealed that high level of TIM expression was an independent prognostic factor of survival time in the ESCC patients in our database. In addition, TIM accumulation and infiltration of CD8+T cells were shown to be negatively correlated. Conclusions This work revealed that TIM are related to prognosis in patients with EC and TIM may be an independent prognostic factor for EC.
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Affiliation(s)
- Hang Yin
- The Department of Radiotherapy Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaoyuan Wang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Nannan Jin
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaodong Ling
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xue Leng
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Wang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Keru Ma
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiangyu Jiang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jinhong Zhu
- Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jianqun Ma
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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Wang J, Wang X, Guo Y, Ye L, Li D, Hu A, Cai S, Yuan B, Jin S, Zhou Y, Li Q, Zheng L, Tong Q. Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression. Clin Transl Med 2021; 11:e588. [PMID: 34841706 PMCID: PMC8567044 DOI: 10.1002/ctm2.588] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/24/2021] [Accepted: 09/14/2021] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND As a metabolic reprogramming feature, cancer cells derive most of their energy from aerobic glycolysis, while its regulatory mechanisms and therapeutic strategies continue to be illusive. METHODS Integrative analysis of publically available expression profile datasets was used to identify critical transcriptional regulators and their target glycolytic enzymes. The functions and acting mechanisms of transcriptional regulators in cancer cells were investigated by using in vitro and in vivo assays. The Kaplan-Meier curve and log-rank assay were used to conduct the survival study. RESULTS Salmonella pathogenicity island 1 (SPI1/PU.1), a haematopoietic transcription factor, was identified to facilitate glycolytic process, tumourigenesis, invasiveness, as well as metastasis of colon cancer cells, which was interplayed by tumour-associated neutrophils. Mechanistically, neutrophils delivered SPI1 mRNA via extracellular vesicles, resulting in enhanced SPI1 expression of cancer cells. Through physical interaction with SPI1-related protein (SPIB), SPI1 drove expression of glycolytic genes within cancer cells, which in turn induced polarization of neutrophils via glycolytic metabolite lactate. Depletion of neutrophils or SPIB-SPI1 interaction in cancer cells significantly inhibited glycolytic process, tumourigenesis and aggressiveness. Upregulation of SPI1 or SPIB was found to be associated with poor prognosis in patients suffering from colon cancer. CONCLUSIONS Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancerous cells and neutrophils suppresses aerobic glycolysis and progression of cancer.
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Affiliation(s)
- Jianqun Wang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Xiaojing Wang
- Department of Geriatrics, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Yanhua Guo
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Lin Ye
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Dan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Anpei Hu
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Shuang Cai
- Department of Pathology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Boling Yuan
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Shikai Jin
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Yi Zhou
- Department of Pathology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Qilan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
| | - Qiangsong Tong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical CollegeHuazhong University of Science and Technology1277 Jiefang AvenueWuhanHubei Province430022P. R. China
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Tessier‐Cloutier B, Twa DDW, Marzban M, Kalina J, Chun HE, Pavey N, Tanweer Z, Katz RL, Lum JJ, Salina D. The presence of tumour-infiltrating neutrophils is an independent adverse prognostic feature in clear cell renal cell carcinoma. J Pathol Clin Res 2021; 7:385-396. [PMID: 33665979 PMCID: PMC8185362 DOI: 10.1002/cjp2.204] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/15/2020] [Accepted: 01/12/2021] [Indexed: 01/05/2023]
Abstract
Tumour-promoting inflammation is an emerging hallmark of cancer that is increasingly recognised as a therapeutic target. As a constituent measure of inflammation, tumour-infiltrating neutrophils (TINs) have been associated with inferior prognosis in several cancers. We analysed clinically annotated cohorts of clear cell renal cell carcinoma (ccRCC) to assess the presence of neutrophils within the tumour microenvironment as a function of outcome. We centrally reviewed ccRCC surgical resection and fine-needle aspiration (FNA) specimens, including primary and metastatic sites, from three centres. TINs were scored based on the presence of neutrophils in resection and FNA specimens by two pathologists. TIN count was correlated with tumour characteristics including stage, WHO/ISUP grade, and immunohistochemistry (IHC). In parallel, we performed CIBERSORT analysis of the tumour microenvironment in a cohort of 516 ccRCCs from The Cancer Genome Atlas (TCGA). We included 102 ccRCC cases comprising 65 resection specimens (37 primary and 28 metastatic resection specimens) and 37 FNAs from primary lesions. High TINs were significantly associated with worse overall survival (p = 0.009) independent of tumour grade and stage. In ccRCCs sampled via FNA, all cases with high TINs had distant metastasis, whereas they were seen in only 19% of cases with low TINs (p = 0.0003). IHC analysis showed loss of E-cadherin in viable tumour cells in areas with high TINs, and neutrophil activation was associated with elastase and citrullinated histone H3 expression (cit-H3). In the TCGA cohort, neutrophilic markers were also associated with worse survival (p < 0.0001). TINs are an independent predictor of worse prognosis in ccRCC, which have the potential to be assessed at the time of first biopsy or FNA. Neutrophils act directly on tumour tissue by releasing elastase, a factor that contributes to the breakdown of cell-cell adhesion and to facilitate tumour dissemination.
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Affiliation(s)
- Basile Tessier‐Cloutier
- Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBCCanada
- Department of Pathology and Laboratory MedicineVancouver General HospitalVancouverBCCanada
| | - David DW Twa
- Faculty of MedicineUniversity of British ColumbiaVancouverBCCanada
| | - Mahsa Marzban
- Life Science InstituteUniversity of British ColumbiaVancouverBCCanada
| | - Jennifer Kalina
- The Trev & Joyce Deeley Research CentreBC CancerVictoriaBCCanada
| | - Hye‐Jung E Chun
- Canada's Michael Smith Genome Sciences CentreBC CancerVancouverBCCanada
| | - Nils Pavey
- Department of Pathology and Laboratory MedicineRoyal Jubilee HospitalVictoriaBCCanada
| | - Zaidi Tanweer
- Department of PathologyThe University of Texas M. D. Anderson Cancer CenterHoustonTXUSA
| | - Ruth L Katz
- Department of PathologyThe University of Texas M. D. Anderson Cancer CenterHoustonTXUSA
| | - Julian J Lum
- The Trev & Joyce Deeley Research CentreBC CancerVictoriaBCCanada
- Department of Biochemistry and MicrobiologyUniversity of VictoriaVictoriaBCCanada
| | - Davide Salina
- Department of Pathology and Laboratory MedicineRoyal Jubilee HospitalVictoriaBCCanada
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Mattiola I. Immune Circuits to Shape Natural Killer Cells in Cancer. Cancers (Basel) 2021; 13:cancers13133225. [PMID: 34203391 PMCID: PMC8267947 DOI: 10.3390/cancers13133225] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Natural killer (NK) cells are circulating innate lymphocytes endowed with antitumoral functions. NK cells are the innate counterpart of effector T cells and among the first cells responding to infections and tumors. In this review, the immune circuits regulating the NK cell antitumoral functions and the possible strategies to shape natural killing in cancer will be discussed. Abstract Natural killer (NK) cells are innate lymphoid cells playing an important role in anti-cancer immunity. NK cells are efficient in controlling the spreading of metastasis but are not very powerful in fighting against primary tumors. The NK cell capability to infiltrate and persist in the tumor microenvironment and to exert their antitumoral functions is often limited by tumor escape mechanisms. These tumor-mediated strategies not only induce NK cell tolerance but also interfere with the NK cell-dependent immune networking. This review will provide an overview of the tumor escape mechanisms impacting NK cells, identify the immune circuits regulating the NK cell-dependent antitumor immunity and revise the emerging therapeutic approaches to unleash NK cells in cancer.
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Affiliation(s)
- Irene Mattiola
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany;
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany
- Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Charitéplatz 1, 10117 Berlin, Germany
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Sato S, Kunisaki C, Takahashi M, Kubo H, Tsuchiya N, Sato K, Miyamoto H, Tamura Y, Kondo H, Tanaka Y, Kasahara K, Kosaka T, Akiyama H, Saigusa Y, Endo I. High postoperative neutrophil-lymphocyte ratio and low preoperative lymphocyte-monocyte ratio predict poor prognosis in gastric cancer patients receiving gastrectomy with positive lavage cytology: a retrospective cohort study. Langenbecks Arch Surg 2021; 406:2295-2303. [PMID: 34137915 DOI: 10.1007/s00423-021-02233-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/06/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Long-term outcomes in gastric cancer patients with positive lavage cytology (CY1) are generally poor. This multi-institutional retrospective cohort study aims to evaluate the clinical significance of the neutrophil-lymphocyte ratio (NLR) and the lymphocyte-monocyte ratio (LMR) in CY1 gastric cancer patients. METHODS A total of 121 CY1 gastric cancer patients without other non-curative factors, who underwent macroscopically curative resection, were enrolled in this study. The cutoff values of preoperative NLR (pre-NLR), postoperative NLR (post-NLR), preoperative LMR (pre-LMR), and postoperative LMR (post-LMR) were defined by the Contal and O'Quigley method as 2.3, 3.0, 2.5, and 3.2, respectively. A Cox proportional hazard model was used to identify the independent prognostic factors among NLR, LMR, and other clinicopathological factors. RESULTS There were significant differences in the overall survival (OS) between the two groups: high post-NLR groups vs. low post-NLR group (median survival time, months) (10.9 vs. 22.8, P = 0.006) and high pre-LMR group vs. low pre-LMR group (21.3 vs. 11.0, P = 0.001). The LMR value elevated significantly after gastrectomy (P = 0.020), although not in the NLR value (P = 0.733). On multivariate analysis, high post-NLR (hazard ratio = 1.506; 95% confidence interval = 1.047-2.167; P = 0.027), low pre-LMR (1.773; 1.135-2.769, 0.012), and no postoperative chemotherapy (1.558; 1.053-2.305, 0.027) were found to be independent prognostic factors for adverse OS. CONCLUSIONS Because a combination of high post-NLR and low pre-LMR may be an adverse prognostic marker in resectable CY1 gastric cancer patients, it is necessary to conduct a prospective trial to confirm a useful perioperative chemotherapeutic regimen for these patients.
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Affiliation(s)
- Sho Sato
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan.
| | - Masazumi Takahashi
- Department of Gastroenterological Surgery, Yokohama Municipal Citizen's Hospital, Yokohama City , Kanagawa, 236-0004, Japan
| | - Hirokazu Kubo
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan
| | - Nobuhiro Tsuchiya
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan
| | - Kei Sato
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan
| | - Hiroshi Miyamoto
- Department of Surgery, Gastroenterological Center, Yokohama City University, 4-57 Urafune-cho, Minami-ku, Yokohama City , Kanagawa, 232-0024, Japan
| | - Yuko Tamura
- Department of Gastroenterological Surgery, Yokohama Municipal Citizen's Hospital, Yokohama City , Kanagawa, 236-0004, Japan
| | - Hiroki Kondo
- Department of Gastroenterological Surgery, Yokohama Municipal Citizen's Hospital, Yokohama City , Kanagawa, 236-0004, Japan
| | - Yusaku Tanaka
- Department of Gastroenterological Surgery, Yokohama Municipal Citizen's Hospital, Yokohama City , Kanagawa, 236-0004, Japan
| | - Kohei Kasahara
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan
| | - Takashi Kosaka
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan
| | - Hirotoshi Akiyama
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan
| | - Yusuke Saigusa
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan
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Hu Z, Xu X, Wei H. The Adverse Impact of Tumor Microenvironment on NK-Cell. Front Immunol 2021; 12:633361. [PMID: 34177887 PMCID: PMC8226132 DOI: 10.3389/fimmu.2021.633361] [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: 11/25/2020] [Accepted: 05/19/2021] [Indexed: 01/22/2023] Open
Abstract
NK cells are considered an important component of innate immunity, which is the first line of defensing against tumors and viral infections in the absence of prior sensitization. NK cells express an array of germline-encoded receptors, which allow them to eliminate abnormal cells and were previously considered a homogenous population of innate lymphocytes, with limited phenotypic and functional diversity. Although their characteristics are related to their developmental origins, other factors, such as tumors and viral infections, can influence their phenotype. Here, we provide an overview of NK cells in the context of the tumor microenvironment, with a primary focus on their phenotypes, functions, and roles in tumor micro-environment. A comprehensive understanding of NK cells in the tumor microenvironment will provide a theoretical basis for the development of NK cell immunotherapy.
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Affiliation(s)
- Ziming Hu
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Life Science and Medicine, University of Science and Technology of China, Heifei, China.,Institute of Immunology, University of Science and Technology of China, Heifei, China
| | - Xiuxiu Xu
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Life Science and Medicine, University of Science and Technology of China, Heifei, China.,Institute of Immunology, University of Science and Technology of China, Heifei, China
| | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Life Science and Medicine, University of Science and Technology of China, Heifei, China.,Institute of Immunology, University of Science and Technology of China, Heifei, China
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Poznanski SM, Singh K, Ritchie TM, Aguiar JA, Fan IY, Portillo AL, Rojas EA, Vahedi F, El-Sayes A, Xing S, Butcher M, Lu Y, Doxey AC, Schertzer JD, Hirte HW, Ashkar AA. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab 2021; 33:1205-1220.e5. [PMID: 33852875 DOI: 10.1016/j.cmet.2021.03.023] [Citation(s) in RCA: 158] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 01/13/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.
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Affiliation(s)
- Sophie M Poznanski
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Kanwaldeep Singh
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
| | - Tyrah M Ritchie
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Jennifer A Aguiar
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Isabella Y Fan
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Ana L Portillo
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Eduardo A Rojas
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Fatemeh Vahedi
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Abdullah El-Sayes
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Sansi Xing
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Martin Butcher
- Juravinski Cancer Centre & McMaster University, Hamilton, ON L8V 5C2, Canada
| | - Yu Lu
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Andrew C Doxey
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Hal W Hirte
- Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada; Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, ON L8V 5C2, Canada
| | - Ali A Ashkar
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada.
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Chen L, Yin L, Qi Z, Li J, Wang X, Ma K, Liu X. Gene expression-based immune infiltration analyses of renal cancer and their associations with survival outcome. BMC Cancer 2021; 21:595. [PMID: 34030645 PMCID: PMC8146654 DOI: 10.1186/s12885-021-08244-2] [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: 03/20/2020] [Accepted: 04/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Renal cancer is a common malignant tumor with an increasing incidence rate. METHODS In this study, based on the gene expression profiles, we analyzed the compositions of tumor-infiltrating immune cells (TIICs) in renal cancer and paracancerous samples using CIBERSORT. The proportions of 22 TIICs subsets in 122 paired renal carcinoma and paracancerous samples, and 224 Wilms tumor (WT) samples varied between intragroup and intergroup. RESULTS After analyzed the difference of TIICs composition between renal cancer and paired paracancerous samples, we found that M0 macrophages and CD8 T cells were significantly elevated, while naive B cells were significantly decreased in renal cancer samples compared with paracancerous samples. Survival analysis showed that high overall TIICs proportion, the low proportion of resting mast cells and the high proportion of activated memory CD4 T cells were associated with poor prognosis of renal cancer patients. In addition, 3 clusters were identified by hierarchical clustering analysis, and they presented a distinct prognosis. Cluster 1 had superior survival outcomes, while cluster 2 had an inferior survival outcome. CONCLUSIONS Our study indicated that overall TIICs proportion, certain TIICs subset proportion, including resting mast cells and activated memory CD4 T cells, and distinct cluster patterns were associated with the prognosis of renal cancer, which was significant for the clinical surveillance and treatment of renal cancer.
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Affiliation(s)
- Lei Chen
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Liang Yin
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Zilong Qi
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Jinmin Li
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Xinning Wang
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Kun Ma
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Xiangyang Liu
- Department of Pediatric Surgery, Cangzhou Central Hospital, No.16 Xinhua West Road, Cangzhou, 061000, Hebei, China.
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Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging. Biomedicines 2021; 9:biomedicines9050557. [PMID: 34067700 PMCID: PMC8156987 DOI: 10.3390/biomedicines9050557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/29/2021] [Accepted: 05/14/2021] [Indexed: 01/22/2023] Open
Abstract
Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.
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Kato S, Demura S, Murakami H, Yoshioka K, Shinmura K, Yokogawa N, Shimizu T, Kawahara N, Tsuchiya H. Clinical outcomes and prognostic factors following the surgical resection of renal cell carcinoma spinal metastases. Cancer Sci 2021; 112:2416-2425. [PMID: 33780597 PMCID: PMC8177761 DOI: 10.1111/cas.14902] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
The efficacy of surgical resection in metastatic renal cell carcinoma is an active and important research field in the postcytokine era. Bone metastases, especially in the spine, compromise patient performance status. Metastasectomy is indicated, if feasible, because it helps to achieve the best clinical outcomes possible compared with other treatments. This study examined the postoperative survival and prognostic factors in patients who underwent metastasectomy of spinal lesions. The retrospective study included 65 consecutive patients with metastatic renal cell carcinomas who were operated on by spinal metastasectomy between 1995 and 2017 at our institution. The cancer‐specific survival times from the first spinal metastasectomy to death or the last follow‐up (≥3 years) were determined using Kaplan‐Meier analysis. Potential factors influencing survival were analyzed using Cox proportional hazard models. Planned surgical resection of all the spine tumors was achieved in all patients. Of these, 38 had complete metastasectomy of all visible metastases, including extraspinal lesions. In all patients, the estimated median cancer‐specific survival time was 100 months. The 3‐, 5‐, and 10‐year cancer‐specific survival rates were 77%, 62%, and 48%, respectively. The survival times after spinal metastasectomy were similar in both cytokine and postcytokine groups. In multivariate analyses, postoperative disability, the coexistence of liver metastases, multiple spinal metastases, and incomplete metastasectomy were significant risk factors associated with short‐term survival. Complete metastasectomy, including extraspinal metastases, was associated with improved cancer‐specific survival. Proper patient selection and complete metastasectomy provide a better prognosis in metastatic renal cell carcinoma patients.
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Affiliation(s)
- Satoshi Kato
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Satoru Demura
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hideki Murakami
- Department of Orthopaedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Katsuhito Yoshioka
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kazuya Shinmura
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Noriaki Yokogawa
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Takaki Shimizu
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Norio Kawahara
- Department of Orthopaedic Surgery, Kanazawa Medical University, Kahoku, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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Lin E, Liu X, Liu Y, Zhang Z, Xie L, Tian K, Liu J, Yu Y. Roles of the Dynamic Tumor Immune Microenvironment in the Individualized Treatment of Advanced Clear Cell Renal Cell Carcinoma. Front Immunol 2021; 12:653358. [PMID: 33746989 PMCID: PMC7970116 DOI: 10.3389/fimmu.2021.653358] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/12/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are currently a first-line treatment option for clear cell renal cell carcinoma (ccRCC). However, recent clinical studies have shown that a large number of patients do not respond to ICIs. Moreover, only a few patients achieve a stable and durable response even with combination therapy based on ICIs. Available studies have concluded that the response to immunotherapy and targeted therapy in patients with ccRCC is affected by the tumor immune microenvironment (TIME), which can be manipulated by targeted therapy and tumor genomic characteristics. Therefore, an in-depth understanding of the dynamic nature of the TIME is important for improving the efficacy of immunotherapy or combination therapy in patients with advanced ccRCC. Here, we explore the possible mechanisms by which the TIME affects the efficacy of immunotherapy and targeted therapy, as well as the factors that drive dynamic changes in the TIME in ccRCC, including the immunomodulatory effect of targeted therapy and genomic changes. We also describe the progress on novel therapeutic modalities for advanced ccRCC based on the TIME. Overall, this review provides valuable information on the optimization of combination therapy and development of individualized therapy for advanced ccRCC.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/mortality
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/genetics
- Kidney Neoplasms/immunology
- Kidney Neoplasms/mortality
- Molecular Targeted Therapy/methods
- Precision Medicine/methods
- Progression-Free Survival
- Randomized Controlled Trials as Topic
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
- Enyu Lin
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Xuechao Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanjun Liu
- Department of Immunology, School of Basic Medical Science, Southern Medical University, Guangzhou, China
| | - Zedan Zhang
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Lu Xie
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kaiwen Tian
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiumin Liu
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yuming Yu
- Department of Urology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Geng SK, Fu SM, Ma SH, Fu YP, Zhang HW. Tumor infiltrating neutrophil might play a major role in predicting the clinical outcome of breast cancer patients treated with neoadjuvant chemotherapy. BMC Cancer 2021; 21:68. [PMID: 33446143 PMCID: PMC7809871 DOI: 10.1186/s12885-021-07789-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Background This study was aimed to explore the predictive ability of tumor infiltrating neutrophil (TIN) in patients with breast cancer treated with neoadjuvant chemotherapy (NACT). Furthermore, the significance of TIN’s dynamic change before and after NACT was investigated. Methods Between January 2004 and December 2017, a total of 133 patients with breast cancer who underwent NACT before surgery were enrolled in this retrospective cohort. Eighty-nine of them were able to get the core needle biopsy (CNB) samples and all the pathological samples after surgery were available. TIN was detected by immunohistochemical staining of CD66b. The optimal cut-off value was determined via receiver operating characteristic (ROC) curve analysis. The association of clinicopathologic characteristics and chemotherapy efficiency was analyzed using X2 test or Fisher’s exact test or t-test as appropriate, and the prognostic significances were assessed by univariate and multivariate analyses. Results Patients with higher TIN after NACT were confirmed to be significantly associated with worse prognosis (P = 0.002). After stratifying patients into two groups, high difference group was prone to have better chemotherapy efficiency (P < 0.001) and clinical outcome in both univariate (P = 0.002) and multivariate analyses (P = 0.003). Conclusions In this study, higher TIN after NACT was confirmed to be associated with breast cancer patients’ worse chemotherapy efficiency and shorter disease-free survival (DFS). Furthermore, the TIN’s dynamic change before and after NACT was firstly proved to be a more accurate predictive marker compared with TIN after NACT. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07789-6.
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Affiliation(s)
- Sheng-Kai Geng
- Department of General Surgery, Xuhui District Central Hospital of Shanghai, Shanghai, 200031, China
| | - Shao-Mei Fu
- Department of Breast Surgeon, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, 200011, China
| | - Shi-Hong Ma
- Department of General Surgery, Xuhui District Central Hospital of Shanghai, Shanghai, 200031, China
| | - Yi-Peng Fu
- Department of Breast Surgeon, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, 200011, China.
| | - Hong-Wei Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Abukhiran I, Mott SL, Bellizzi AM, Boukhar SA. Paraneoplastic leukemoid reaction: Case report and review of the literature. Pathol Res Pract 2021; 217:153295. [PMID: 33341546 DOI: 10.1016/j.prp.2020.153295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/18/2020] [Accepted: 11/20/2020] [Indexed: 11/11/2022]
Abstract
OBJECTIVES We recently encountered a patient with unexplained hyperleukocytosis (105.4 K/μL at presentation), subsequently found to have colon cancer with a marked tumor-associated neutrophilic infiltrate; the leukocytosis abruptly improved after tumor removal. Paraneoplastic leukemoid reaction (PLR) is a rare entity, occurring due to tumor cytokine secretion (typically granulocyte-colony stimulating factor [G-CSF]). We describe a case and aggregate results of previously published cases. METHODS We reviewed the English-language literature for all prior reports of PLR, recording age, gender, histologic diagnosis, WBC count, G-CSF level, and overall survival. We analyzed clinicopathologic variables' impact on survival. RESULTS We identified 179 cases (mean age 64; 72 % M). Adeno-, squamous cell, sarcomatoid, and undifferentiated carcinomas accounted for >70 %. Esophagus, gallbladder, lung, liver, and pancreas were the most common primaries. At time of publication 81 % of patients had died, with mean overall survival of 4 months. There was no correlation between WBC count and G-CSF level. On univariate analysis, WBC count was the only variable associated with survival (P = 0.03). Patients with WBC counts >100 K/μL were twice as likely to die as those with counts from 11 K to 40 K/μL. CONCLUSIONS PLR, typically carcinoma-associated, is characterized by dismal prognosis. The WBC count is inversely related to survival. Knowledge of this phenomenon militates against protracted, expensive work ups. In malignant neoplasms with prominent neutrophilic stroma, the pathologist should correlate with the WBC count and, if markedly elevated (>40 K/μL), raise consideration for PLR.
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Affiliation(s)
- Ibrahim Abukhiran
- Department of Pathology, University of Iowa Hospitals and Clinics and Carver College of Medicine, Iowa City, IA, USA
| | - Sarah L Mott
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics and Carver College of Medicine, Iowa City, IA, USA
| | - Andrew M Bellizzi
- Department of Pathology, University of Iowa Hospitals and Clinics and Carver College of Medicine, Iowa City, IA, USA.
| | - Sarag A Boukhar
- Department of Pathology, University of Iowa Hospitals and Clinics and Carver College of Medicine, Iowa City, IA, USA.
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Azuma T, Sato Y, Ohno T, Azuma M, Kume H. Serum soluble B7-H3 is a prognostic marker for patients with non-muscle-invasive bladder cancer. PLoS One 2020; 15:e0243379. [PMID: 33306717 PMCID: PMC7732087 DOI: 10.1371/journal.pone.0243379] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background B7-H3 is a member of the B7 family of immune-regulatory ligands and is a costimulatory molecule promoting the T cell response in vitro. We herein investigated the clinical utility of serum soluble B7-H3 (sB7-H3) in patients with non-muscle invasive bladder cancer (NMIBC). Methods We analyzed 555 patients in whom NMIBC was diagnosed at Tokyo Metropolitan Tama Medical Center between 2008 and 2013. We measured the serum sB7-H3 (sB7-H3) level using the enzyme-linked immunosorbent assay (ELISA) and evaluated the utility of sB7-H3 as a prognostic biomarker for NMIBC. We used the Cox proportional hazards regression model to assess recurrence-free survival (RFS) and progression-free survival (PFS) with the sB7-H3 level. Results We detected high levels of sB7-H3 in the sera of 47% of patients with NMIBC versus only 8% in healthy donors. The increase of sB7-H3 was significantly associated with poor RFS and PFS. Multivariate analysis showed that elevated sB7-H3 was an independent prognostic factor of RFS and PFS. According to the European Organization for Research and Treatment of Cancer (EORTC), in intermediate-low and intermediate-high risk groups, the presence of sB7-H3 significantly determined the rate of recurrence and progression. Conclusions Our data suggested that evaluating serum sB7-H3 expression is a useful tool for predicting the prognosis of patients with NMIBC.
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Affiliation(s)
- Takeshi Azuma
- Department of Urology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Hongo, Tokyo, Japan
- Department of Urology, The University of Tokyo Graduate School of Medicine, Hongo, Tokyo, Japan
- * E-mail:
| | - Yujiro Sato
- Department of Urology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan
| | - Tatsukuni Ohno
- Oral Health Science Center, Tokyo Dental College, Chiyoda, Tokyo, Japan
| | - Miyuki Azuma
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Hongo, Tokyo, Japan
| | - Haruki Kume
- Department of Urology, The University of Tokyo Graduate School of Medicine, Hongo, Tokyo, Japan
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Li K, Peng YG, Yan RH, Song WQ, Peng XX, Ni X. Age-dependent changes of total and differential white blood cell counts in children. Chin Med J (Engl) 2020; 133:1900-1907. [PMID: 32826452 PMCID: PMC7462212 DOI: 10.1097/cm9.0000000000000854] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Total and differential white blood cell counts are important for the diagnostic evaluation of suspected diseases. To facilitate the interpretation of total and differential white blood cell counts in pediatric patients, the present study investigated age-dependent changes in total and differential white blood cell counts in healthy reference children. METHODS Data were obtained from the Pediatric Reference Intervals in China study (PRINCE), which aims to establish and verify pediatric reference intervals for Chinese children based on a nationwide multicenter cross-sectional study from January 2017 to December 2018. Quantile curves were calculated using the generalized additive models for location, shape, and scale method. The 2.5th, 50th, and 97.5th quantile curves were calculated for both total and differential white blood counts. Percents of stacked area charts were used to demonstrate the proportions of differential white blood cells. All statistical analyses were performed using R software. RESULTS Both 50th and 97.5th quantiles of total white blood cell count and monocyte count were highest at birth, then rapidly decreased in the first 6 months of life; relatively slow reduction continued until 2 years of age. The lymphocyte count was low during infancy and increased to its highest level at 6 months of age; it then exhibited moderate and continuous reduction until approximately 9 years of age. The pattern of neutrophil count changed with age in a manner opposite to that of lymphocyte count. Besides, there were two inter-sections of lymphocyte count and neutrophil count during infancy and at approximately 5 years of age, based on locally weighted regression (LOESS) analysis. There were no apparent age-related changes in eosinophil or basophil counts. CONCLUSION These data regarding age-related changes in total and differential white blood cell counts can be used to assess the health of pediatric patients and guide clinical decisions.
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Affiliation(s)
- Kun Li
- Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Ya-Guang Peng
- Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
| | - Ruo-Hua Yan
- Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
| | - Wen-Qi Song
- Department of Clinical Laboratory Center, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
| | - Xiao-Xia Peng
- Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Xin Ni
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck, Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children Health, Beijing 100045, China
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Miyazato K, Tahara H, Hayakawa Y. Antimetastatic effects of thalidomide by inducing the functional maturation of peripheral natural killer cells. Cancer Sci 2020; 111:2770-2778. [PMID: 32573072 PMCID: PMC7419051 DOI: 10.1111/cas.14538] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/11/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022] Open
Abstract
Thalidomide and its analogues are known as immunomodulatory drugs (IMiDs) that possess direct antimyeloma effects, in addition to other secondary effects, including antiangiogenic, antiinflammatory, and immunomodulatory effects. Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both γ‐interferon (IFN‐γ) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide‐treated mice, there was a significant increase in the terminally differentiated mature CD27lo NK cells in the peripheral tissues and NK cells in thalidomide‐treated mice showed significantly higher cytotoxicity and IFN‐γ production. The NK cell expression of T‐bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase‐3β expression was observed in thalidomide‐treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T‐bet expression to inhibit lung metastasis of cancer cells.
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Affiliation(s)
- Kiho Miyazato
- Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Hideaki Tahara
- Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Cancer Drug Discovery and Development, Osaka International Cancer Center, Osaka, Japan
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48
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Natural killer and NKT cells in the male reproductive tract. J Reprod Immunol 2020; 142:103178. [PMID: 32739646 DOI: 10.1016/j.jri.2020.103178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 07/01/2020] [Accepted: 07/09/2020] [Indexed: 01/01/2023]
Abstract
Natural killer (NK) cells are important effector lymphocytes that play a pivotal role in the innate and adaptive immune responses to tumors and viral infection. NKT cells are a heterogeneous group of T cells that share properties with both T cells and NK cells. They display immunoregulatory properties as they facilitate the cell-mediated immune response to tumors and infectious diseases, and inhibit cell-mediated immunity associated with autoimmune diseases and allograft rejection. However, the roles of NK and NKT cells in the male reproductive tract remain largely unexplored, in particular, NKT cells, tissue distribution, and state of health or disease. Infection and inflammation of the male genital tract are thought to be the primary etiological factors of male infertility. In this review, we considered this complex and rapidly growing field. We summarize the recent findings and the characterization and roles of NK and NKT cells in the male reproductive tract, including the testis, epididymis, prostate, seminal vesicle, and semen, to enhance our understanding of the immunological mechanisms of male infertility and for the design effective vaccines for male reproductive health in the future.
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Drljevic-Nielsen A, Rasmussen F, Mains JR, Thorup K, Donskov F. Baseline blood volume identified by dynamic contrast-enhanced computed tomography as a new independent prognostic factor in metastatic renal cell carcinoma. Transl Oncol 2020; 13:100829. [PMID: 32653813 PMCID: PMC7350156 DOI: 10.1016/j.tranon.2020.100829] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 11/21/2022] Open
Abstract
Background Preliminary data showed prognostic impact of contrast-enhanced computed tomography (DCE-CT) identified Blood Volume (BV) in patients with metastatic renal cell carcinoma (mRCC). BV as an independent prognostic factor remains to be assessed. Materials and Methods DCE-CT identified BV was prospectively quantified in patients with mRCC receiving first line therapies, adjusted for International mRCC Database Consortium (IMDC) individual features and treatments, and associated with overall survival (OS), progression-free survival (PFS) and objective response (ORR), using Cox and logistic regression, respectively. Results 105 patients with mRCC were included. Median baseline BV was 32.87 mL × 100 g−1 (range 9.52 to 92.87 mL × 100 g−1). BV above median was associated with IMDC favorable risk category (P = 0.004), metastasis free interval ≥ 1 year (P = 0.007), male gender (P = 0.032), normal hemoglobin (P = 0.040) and normal neutrophils (P = 0.007), whereas low BV was associated with poor risk IMDC features (P < 0.05). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, P = 0.015) and longer OS (42.2 vs. 22.4 months, P = 0.001), respectively. In multivariate analysis high baseline BV remained independent favorable for OS (HR 0.49, 95% CI 0.30–0.78, P = 0.003) and PFS (HR 0.64; 95% CI 0.42–0.97, P = 0.036). BV as a continuous variable was also associated with OS in the multivariate analysis (HR 0.98, 95% CI 0.96–1.00, P = 0.017). The estimated concordance index (c-index) was 0.688 using IMDC score and 0.701 when BV was added. Conclusions DCE-CT identified Blood Volume is a new, independent prognostic factor in mRCC, which may improve the prognostic accuracy of IMDC.
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Affiliation(s)
- Aska Drljevic-Nielsen
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
| | - Finn Rasmussen
- Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
| | - Jill R Mains
- Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
| | - Kennet Thorup
- Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
| | - Frede Donskov
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
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Zhang S, Liu W, Hu B, Wang P, Lv X, Chen S, Shao Z. Prognostic Significance of Tumor-Infiltrating Natural Killer Cells in Solid Tumors: A Systematic Review and Meta-Analysis. Front Immunol 2020; 11:1242. [PMID: 32714321 PMCID: PMC7343909 DOI: 10.3389/fimmu.2020.01242] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 05/18/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues. Methods: PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance. Results : Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315–0.710, p < 0.001; HR = 0.484, 95%CI: 0.380–0.616, p < 0.001; HR = 0.34, 95%CI: 0.14–0.80, p = 0.014; HR = 0.622, 95%CI: 0.470–0.821, p < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261–0.531, p < 0.001; HR = 0.525, 95%CI: 0.346–0.797, p = 0.003; HR = 0.559, 95%CI: 0.385–0.812, p = 0.002, respectively). Conclusions : Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.
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Affiliation(s)
- Shuo Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijian Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binwu Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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