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Yang M, Lin W, Huang J, Mannucci A, Luo H. Novel immunotherapeutic approaches in gastric cancer. PRECISION CLINICAL MEDICINE 2024; 7:pbae020. [PMID: 39397869 PMCID: PMC11467695 DOI: 10.1093/pcmedi/pbae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/08/2024] [Accepted: 09/08/2024] [Indexed: 10/15/2024] Open
Abstract
Gastric cancer is a malignant tumor that ranks third in cancer-related deaths worldwide. Early-stage gastric cancer can often be effectively managed through surgical resection. However, the majority of cases are diagnosed in advanced stages, where outcomes with conventional radiotherapy and chemotherapy remain unsatisfactory. Immunotherapy offers a novel approach to treating molecularly heterogeneous gastric cancer by modifying the immunosuppressive tumor microenvironment. Immune checkpoint inhibitors and adoptive cell therapy are regarded as promising modalities in cancer immunotherapy. Food and Drug Administration-approved programmed death-receptor inhibitors, such as pembrolizumab, in combination with chemotherapy, have significantly extended overall survival in gastric cancer patients and is recommended as a first-line treatment. Despite challenges in solid tumor applications, adoptive cell therapy has demonstrated efficacy against various targets in gastric cancer treatment. Among these approaches, chimeric antigen receptor-T cell therapy research is the most widely explored and chimeric antigen receptor-T cell therapy targeting claudin18.2 has shown acceptable safety and robust anti-tumor capabilities. However, these advancements primarily remain in preclinical stages and further investigation should be made to promote their clinical application. This review summarizes the latest research on immune checkpoint inhibitors and adoptive cell therapy and their limitations, as well as the role of nanoparticles in enhancing immunotherapy.
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Affiliation(s)
- Meng Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Wuhao Lin
- Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jiaqian Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Emndoscopy Unit, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan 20132, Italy
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope; Monrovia, CA 91016, USA
| | - Huiyan Luo
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
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Matsuoka T, Yashiro M. Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment. Int J Mol Sci 2024; 25:11735. [PMID: 39519285 PMCID: PMC11546171 DOI: 10.3390/ijms252111735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/23/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of tumor cells, and interactions between the cellular and molecular components of the TME-e.g., inflammatory cells, fibroblasts, vasculature cells, and innate and adaptive immune cells-promote the aggressiveness of cancer cells and dissemination to distant organs. This review summarizes the roles of various TME cells and molecules in regulating the malignant progression and metastasis of GC. We also address the important roles of signaling pathways in mediating the interaction between cancer cells and the different components of the GC TME. Finally, we discuss the implications of these molecular mechanisms for developing novel and effective therapies targeting molecular and cellular components of the GC TME to control the malignant progression of GC.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 5458585, Japan;
- Institute of Medical Genetics, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 5458585, Japan;
- Institute of Medical Genetics, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 5458585, Japan
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Li Y, Wu D, Xu A, Xu M, Fu B, Xiong W. Exploring the effect of NK-cell related molecules on the prognosis and tumor microenvironment of gastric cancer patients: Evidence from large sample populations. Heliyon 2024; 10:e33759. [PMID: 39071629 PMCID: PMC11276922 DOI: 10.1016/j.heliyon.2024.e33759] [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: 01/08/2024] [Revised: 06/17/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024] Open
Abstract
Background Natural killer (NK) cells play a significant role in anti-tumor immunity, and their involvement has been documented in various cancers. However, a deeper understanding of the mechanisms by which NK cells influence gastric cancer progression remains necessary. Methods We utilized the Cancer Genome Atlas (TCGA) database to acquire transcriptional profiles, clinical information, and mutation data for gastric cancer patients. R software and associated packages were employed for all analyses of this publicly available data. Results We used multiple algorithms to evaluate the tumor microenvironment in gastric cancer samples. We performed differential expression analysis to pinpoint genes related to NK cells. Utilizing this data, we developed a prognostic model featuring three crucial NK cell-related genes: MAB21L2, ARPP21, and MUCL1. This model showed strong predictive performance in the training and validation groups. Consistently, patients identified as high-risk according to our model had worse overall survival rates. To further elucidate the biological differences between high-risk and low-risk patients, we performed enrichment analyses focusing on biological pathways and immune-related factors. Additionally, we observed a correlation between higher risk scores and non-responsiveness to treatment. Interestingly, high-risk patients were found to be potentially more sensitive to axitinib. We selected MUCL1 for further investigation due to its potential role in the model. While MUCL1 mRNA levels were elevated in both gastric cancer and paired normal tissues, protein expression analysis using the Human Protein Atlas database revealed a decrease in MUCL1 protein levels within tumor tissues. Conclusions Our findings contribute to a more comprehensive understanding of the role of NK cells in gastric cancer and highlight MUCL1 as a promising therapeutic target.
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Affiliation(s)
- Yuqin Li
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong New District, Shanghai, 201399, China
| | - Dejun Wu
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
- Department of Gastrointestinal Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
| | - Anjun Xu
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
- Department of Gastrointestinal Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
| | - Ming Xu
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
- Department of Gastrointestinal Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, China
| | - Baiqing Fu
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong New District, Shanghai, 201399, China
| | - Wujun Xiong
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong New District, Shanghai, 201399, China
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Baugh R, Khalique H, Page E, Lei-Rossmann J, Wan PKT, Johanssen T, Ebner D, Ansorge O, Seymour LW. Targeting NKG2D ligands in glioblastoma with a bispecific T-cell engager is augmented with conventional therapy and enhances oncolytic virotherapy of glioma stem-like cells. J Immunother Cancer 2024; 12:e008460. [PMID: 38724464 PMCID: PMC11086472 DOI: 10.1136/jitc-2023-008460] [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] [Accepted: 04/11/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Glioblastoma (GBM) almost invariably becomes resistant towards conventional treatment of radiotherapy and temozolomide (TMZ) chemotherapy, partly due to subpopulations of intrinsically resistant glioma stem-like cells (GSC). The oncolytic herpes simplex virus-1 G207 is a promising approach for GBM virotherapy although its efficacy in patients with GBM is often limited. Natural killer group 2 member D ligands (NKG2DLs) are minimally expressed by healthy cells but are upregulated by the DNA damage response (DDR) and in malignant cells with chronic DDR signaling, resulting in innate immune activation. METHODS We have designed a bispecific T-cell engager (BiTE) capable of cross-linking CD3 on T cells with NKG2DL-expressing GBM cells. We then engineered the G207 virus to express the NKG2D BiTE and secrete it from infected cells. The efficacy of the free BiTE and BiTE delivered by G207 was evaluated in combination with conventional therapies in GBM cells and against patient-derived GSCs in the context of T-cell activation and target cell viability. RESULTS NKG2D BiTE-mediated cross-linking of GBM cells and T cells causes antigen-independent T-cell activation, pro-inflammatory cytokine release, and tumor cell death, thereby combining direct viral oncolysis with BiTE-mediated cytotoxicity. Surface NKG2DL expression was further elevated on GBM cells following pretreatment with sublethal doses of TMZ and radiation to induce the DDR, increasing sensitivity towards G207-NKG2D BiTE and achieving synergistic cytotoxicity. We also demonstrate a novel strategy for targeting GSCs that are non-permissive to G207 infection but remain sensitive to NKG2D BiTE. CONCLUSIONS We propose a potential model for targeting GSCs in heterogeneous tumors, whereby differentiated GBM cells infected with G207-NKG2D BiTE produce NKG2D BiTE locally, directing T-cell cytotoxicity towards the GSC subpopulations in the tumor microenvironment.
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Affiliation(s)
- Richard Baugh
- Department of Oncology, University of Oxford, Oxford, UK
| | - Hena Khalique
- Department of Oncology, University of Oxford, Oxford, UK
| | - Emma Page
- Department of Oncology, University of Oxford, Oxford, UK
| | | | | | - Timothy Johanssen
- Target Discovery Institute, University of Oxford Nuffield Department of Medicine, Oxford, UK
| | - Daniel Ebner
- Target Discovery Institute, University of Oxford Nuffield Department of Medicine, Oxford, UK
| | - Olaf Ansorge
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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Seller A, Tegeler CM, Mauermann J, Schreiber T, Hagelstein I, Liebel K, Koch A, Heitmann JS, Greiner SM, Hayn C, Dannehl D, Engler T, Hartkopf AD, Hahn M, Brucker SY, Salih HR, Märklin M. Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome. Int J Mol Sci 2024; 25:4126. [PMID: 38612935 PMCID: PMC11012452 DOI: 10.3390/ijms25074126] [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: 03/08/2024] [Revised: 04/02/2024] [Accepted: 04/05/2024] [Indexed: 04/14/2024] Open
Abstract
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.
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Affiliation(s)
- Anna Seller
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Christian M. Tegeler
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
- Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Jonas Mauermann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Tatjana Schreiber
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Ilona Hagelstein
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Kai Liebel
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - André Koch
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Jonas S. Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
- Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Sarah M. Greiner
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Clara Hayn
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Dominik Dannehl
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Tobias Engler
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Andreas D. Hartkopf
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Markus Hahn
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Sara Y. Brucker
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Helmut R. Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
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Anthofer M, Windisch M, Haller R, Ehmann S, Wrighton S, Miller M, Schernthanner L, Kufferath I, Schauer S, Jelušić B, Kienesberger S, Zechner EL, Posselt G, Vales-Gomez M, Reyburn HT, Gorkiewicz G. Immune evasion by proteolytic shedding of natural killer group 2, member D ligands in Helicobacter pylori infection. Front Immunol 2024; 15:1282680. [PMID: 38318189 PMCID: PMC10839011 DOI: 10.3389/fimmu.2024.1282680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/02/2024] [Indexed: 02/07/2024] Open
Abstract
Background Helicobacter pylori (H. pylori) uses various strategies that attenuate mucosal immunity to ensure its persistence in the stomach. We recently found evidence that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system. The NKG2D receptor and its ligands are a major activation system of natural killer and cytotoxic T cells, which are important for mucosal immunity and tumor immunosurveillance. The NKG2D system allows recognition and elimination of infected and transformed cells, however viruses and cancers often subvert its activation. Here we aimed to identify a potential evasion of the NKG2D system in H. pylori infection. Methods We analyzed expression of NKG2D system genes in gastric tissues of H. pylori gastritis and gastric cancer patients, and performed cell-culture based infection experiments using H. pylori isogenic mutants and epithelial and NK cell lines. Results In biopsies of H. pylori gastritis patients, NKG2D receptor expression was reduced while NKG2D ligands accumulated in the lamina propria, suggesting NKG2D evasion. In vitro, H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells, and these effects were associated with specific H. pylori virulence factors. The H. pylori-driven release of soluble NKG2D ligands reduced the immunogenic visibility of infected cells and attenuated the cytotoxic activity of effector immune cells, specifically the anti-tumor activity of NK cells. Conclusion H. pylori manipulates the NKG2D system. This so far unrecognized strategy of immune evasion by H. pylori could potentially facilitate chronic bacterial persistence and might also promote stomach cancer development by allowing transformed cells to escape immune recognition and grow unimpeded to overt malignancy.
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Affiliation(s)
- Margit Anthofer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Markus Windisch
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Rosa Haller
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Sandra Ehmann
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Michael Miller
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Iris Kufferath
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Silvia Schauer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Barbara Jelušić
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Sabine Kienesberger
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
| | - Ellen L. Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria
| | - Mar Vales-Gomez
- Department of Immunology and Oncology, Spanish National Centre for Biotechnology, Madrid, Spain
| | - Hugh T. Reyburn
- Department of Immunology and Oncology, Spanish National Centre for Biotechnology, Madrid, Spain
| | - Gregor Gorkiewicz
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
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Zheng S, Li H, Li Y, Chen X, Shen J, Chen M, Zhang C, Wu J, Sun Q. The emerging role of glycolysis and immune evasion in gastric cancer. Cancer Cell Int 2023; 23:317. [PMID: 38071310 PMCID: PMC10710727 DOI: 10.1186/s12935-023-03169-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/27/2023] [Indexed: 08/21/2024] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC.
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Affiliation(s)
- Shanshan Zheng
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Huaizhi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Yaqi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Xu Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Junyu Shen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Menglin Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Cancan Zhang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Jian Wu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
| | - Qingmin Sun
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
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8
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Mao D, Zhou Z, Chen H, Liu X, Li D, Chen X, He Y, Liu M, Zhang C. Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer. Cancer Lett 2023; 572:216351. [PMID: 37591356 DOI: 10.1016/j.canlet.2023.216351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/08/2023] [Accepted: 08/13/2023] [Indexed: 08/19/2023]
Abstract
Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays a critical role in tumour progression, but its role in immune escape in gastric cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes in a GC cell line that was resistant to the antitumor effect of Natural killer (NK) cells. Apoptosis and the expression of IFN-γ and TNF-α were detected by flow cytometry (FCM). PLEK2 expression was examined by Western blotting and immunohistochemistry (IHC). PLEK2 was upregulated in MGC803R cells that were resistant to the antitumor effect of NK cells. PLEK2 knockout increased the sensitivity of GC cells to NK cell killing. PLEK2 expression was negatively correlated with MICA and positively correlated with MT1-MMP expression both in vitro and in vivo. PLEK2 promoted Sp1 phosphorylation through the PI3K-AKT pathway, thereby upregulating MT1-MMP expression, which ultimately led to MICA shedding. In mouse xenograft models, PLEK2 knockout inhibited intraperitoneal metastasis of GC cells and promoted NK cell infiltration. In summary, PLEK2 suppressed NK cell immune surveillance by promoting MICA shedding, which serves as a potential therapeutic target for GC.
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Affiliation(s)
- Deli Mao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Zhijun Zhou
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United States
| | - Hengxing Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Xinran Liu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Dongsheng Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Xiancong Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China.
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Liu Y, Li C, Lu Y, Liu C, Yang W. Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer. Front Immunol 2022; 13:1016817. [PMID: 36341377 PMCID: PMC9630479 DOI: 10.3389/fimmu.2022.1016817] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/07/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.
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Affiliation(s)
- Yuanda Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
| | - Yaoping Lu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chang Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
- *Correspondence: Changfeng Li, ; Wei Yang,
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Godoy‑Pacheco A, García‑Chagollán M, Ramírez‑De‑Arellano A, Hernández‑Silva C, Villegas‑Pineda J, Ramírez‑López I, Zepeda‑Nuño J, Aguilar‑Lemarroy A, Pereira‑Suárez A. Differential modulation of natural killer cell cytotoxicity by 17β‑estradiol and prolactin through the NKG2D/NKG2DL axis in cervical cancer cells. Oncol Lett 2022; 24:288. [DOI: 10.3892/ol.2022.13408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/19/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Alejandro Godoy‑Pacheco
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Mariel García‑Chagollán
- Institute for Research in Biomedical Sciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Adrián Ramírez‑De‑Arellano
- Institute for Research in Biomedical Sciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Christian Hernández‑Silva
- Institute for Research in Biomedical Sciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Julio Villegas‑Pineda
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Inocencia Ramírez‑López
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - José Zepeda‑Nuño
- Center for Research and Diagnosis of Pathology, Department of Microbiology and Pathology, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Adriana Aguilar‑Lemarroy
- Department of Immunology, Western Biomedical Research Center, Guadalajara, Jalisco 44340, Mexico
| | - Ana Pereira‑Suárez
- Institute for Research in Biomedical Sciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
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11
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Advances of research of Fc-fusion protein that activate NK cells for tumor immunotherapy. Int Immunopharmacol 2022; 109:108783. [PMID: 35561479 DOI: 10.1016/j.intimp.2022.108783] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/02/2022] [Accepted: 04/14/2022] [Indexed: 12/21/2022]
Abstract
The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.
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12
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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Wang J, Loeuillard E, Gores GJ, Ilyas SI. Cholangiocarcinoma: what are the most valuable therapeutic targets - cancer-associated fibroblasts, immune cells, or beyond T cells? Expert Opin Ther Targets 2021; 25:835-845. [PMID: 34806500 DOI: 10.1080/14728222.2021.2010046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION CCAs are dense and desmoplastic tumors with an abundant tumor microenviroment (TME). The evolving TME is characterized by reciprocal interactions between cancer cells and their environment and is essential in facilitating tumor progression. The TME has nonimmune and immune components. Nonimmune cell types include cancer-associated fibroblasts (CAFs) and endothelial cells accompanying tumor angiogenesis. Immune cell types include elements of the innate and adaptive immune response, and can have pro-tumor or antitumor roles. The TME can shape treatment response and resistance. Therefore, elements of the TME are attractive therapeutic targets. TME targeting therapies have been evaluated in preclinical and clinical studies but only a small subset of patients has a meaningful response. AREAS COVERED We discuss the TME components and potential TME targeting strategies. Literature search was performed on PubMed and ClinicalTrials.gov until October 2021. EXPERT OPINION Elucidating the CCA TME is essential for developing effective treatment strategies. Preclinical models that recapitulate the disease (such as organoids) are important tools in uncovering the intricate cross talk in the CCA TME. Characterization of patient-derived specimens using multi-omic and single-omic technologies can dissect the cellular interplay in the CCA TME, which can guide development of effective treatment strategies and identify biomarkers for patient stratification.
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Affiliation(s)
- Juan Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Emilien Loeuillard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Ke J, Ye J, Li M, Zhu Z. The Role of Matrix Metalloproteinases in Endometriosis: A Potential Target. Biomolecules 2021; 11:1739. [PMID: 34827737 PMCID: PMC8615881 DOI: 10.3390/biom11111739] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 12/14/2022] Open
Abstract
Endometriosis is a condition that is influenced by hormones and involves stroma and glands being found outside the uterus; there are increases in proliferation, invasion, internal bleeding, and fibrosis. Matrix metalloproteinases (MMPs) have been suggested to be crucial in the progression of invasion. The MMP family includes calcium-dependent zinc-containing endopeptidases, some of which not only affect the process of cell invasion but also participate in other physiological and pathological processes, such as angiogenesis and fibrosis. MMPs act as downstream-targeted molecules and their expression can be regulated by numerous factors such as estrogen, oxidative stress, cytokines, and environmental contaminants. Given their unique roles in endometriosis, MMPs may become effective biomarkers of endometriosis in the future. In the present review, we summarize the current literature on MMPs regarding their classification, function, and potential value for endometriosis, which may contribute to our knowledge of MMPs and MMP-targeted interventions.
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Affiliation(s)
- Junya Ke
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China;
- Department of Integrated Traditional & Western Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Jiangfeng Ye
- Division of Obstetrics and Gynecology, KK Women’s and Children’s Hospital, Singapore 229899, Singapore;
| | - Mingqing Li
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China;
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai 200011, China
| | - Zhiling Zhu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China;
- Department of Integrated Traditional & Western Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
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TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells. Cancers (Basel) 2021; 13:cancers13194955. [PMID: 34638439 PMCID: PMC8507839 DOI: 10.3390/cancers13194955] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer patients are characterized by NK cells with altered surface markers, such as CD56 brightness, CD9, CD49a (pro-angiogenic) and PD-1, and TIM-3 (exhaustion), that favor immune escape. Transforming growth factor-beta (TGFβ) is a major tumor-derived cytokine that favors cancer growth and supports pro-angiogenic activities in NK cells by inducing pro-angiogenic molecules. TIMP-1 and TIMP-2 play a crucial role in extracellular matrix (ECM) regulation, wound healing, pregnancy and cancer, and there is increasing evidence that they are immune-modulatory. We found that recombinant TIMP-1 and -2 can partially contrast the induction of pro-tumor/pro-angiogenic decidual-like polarization of NK cells by TGFβ. Abstract Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16−, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP’s new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic–therapeutic roles.
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Liu H, Yao C, Zhang L, Xin J, Zhang Z, Wang S. Nanoliposomes co-encapsulating Ce6 and SB3CT against the proliferation and metastasis of melanoma with the integration of photodynamic therapy and NKG2D-related immunotherapy on A375 cells. NANOTECHNOLOGY 2021; 32:455102. [PMID: 34352746 DOI: 10.1088/1361-6528/ac1afd] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/05/2021] [Indexed: 06/13/2023]
Abstract
Purpose. To overcome the insufficiency of conventional photodynamic therapy (PDT) for treating metastatic melanoma, the combination of smart nanoparticles and PDT with immunotherapy was used to achieve a higher efficiency by accumulating more photosensitizers in tumor areas and triggering stronger immune responses against tumors after PDT.Methods. In this study, we designed a nanoliposome co-encapsulation of chlorin E6 (Ce6) and SB-3CT to realize significant antitumoral proliferation and metastasis efficacy after laser irradiation in A375 cells. The morphology, size distribution, and loading efficiency of Ce6-SB3CT@Liposome (Lip-SC) were characterized. The reactive oxygen species (ROS) generation and cytotoxicity were evaluated in A375 cells, and the mechanisms of natural killer (NK) cell-mediated killing were assessed.Results. Lip-SC showed good stability and was well-dispersed with a diameter of approximately 140 nm in phosphate-buffered saline. The nanoliposomes could accumulate in tumor areas and induce apoptosis in cancer cells upon 660 nm light irradiation, which could trigger an immune response and induce the expression of NK group 2 member D (NKG2D) ligands. The subsequently released SB-3CT could further activate NK cells effectively and strengthen the immune system by inhibiting the shedding of soluble NKG2D ligands.Discussion. Taken together, the synergistic effects of SB-3CT on nanoliposomes for Ce6-mediated PDT were analyzed in detail to provide a new platform for future anti-melanoma treatment.
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Affiliation(s)
- Huifang Liu
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
| | - Cuiping Yao
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
| | - Luwei Zhang
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
- School of Food Equipment Engineering and Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
| | - Jing Xin
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
| | - Zhenxi Zhang
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
| | - Sijia Wang
- Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Republic of China
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Alves E, McLeish E, Blancafort P, Coudert JD, Gaudieri S. Manipulating the NKG2D Receptor-Ligand Axis Using CRISPR: Novel Technologies for Improved Host Immunity. Front Immunol 2021; 12:712722. [PMID: 34456921 PMCID: PMC8397441 DOI: 10.3389/fimmu.2021.712722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/28/2021] [Indexed: 12/26/2022] Open
Abstract
The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.
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Affiliation(s)
- Eric Alves
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA, Australia
| | - Emily McLeish
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
| | - Pilar Blancafort
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA, Australia
- The Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jerome D. Coudert
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
- School of Medicine, University of Notre Dame, Fremantle, WA, Australia
| | - Silvana Gaudieri
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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Fuertes MB, Domaica CI, Zwirner NW. Leveraging NKG2D Ligands in Immuno-Oncology. Front Immunol 2021; 12:713158. [PMID: 34394116 PMCID: PMC8358801 DOI: 10.3389/fimmu.2021.713158] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/02/2021] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.
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Affiliation(s)
- Mercedes Beatriz Fuertes
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Carolina Inés Domaica
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Norberto Walter Zwirner
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.,Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina
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19
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Abstract
Background Transforming growth factor beta (TGF-β) is a typical immuno-inhibitory cytokine and highly secreted by lung cancer cells. It was supposed that its immunosuppressive effects to NK cell might be related with the altered expression of activating and inhibitory molecules in lung cancer cells. In this study, we examined the expression of NKG2DLs, PD-L1 and PD-L2 in lung cancer cells after treatment of TGF-β and a TGF-β inhibitor, Galunisertib (LY2157299). Results TGF-β reduced the level of surface proteins of five NKG2DLs without altered transcription levels in lung cancer cells. Galunisertib reversed the effect of TGF-β on the expression of NKG2DLs. Since MMP inhibitors, MMPi III and MMP2 inhibitor I, restored the reduced expression of NKG2DLs after treatment of TGF-β, it was thought that TGF-β induced the expression of MMP2 which facilitated the shedding of the NKG2DLs in cancer cells. However, the expression of PD-L1, L2 were not changed by treatment with TGF-β or Galunisertib. Conclusions Therefore, inhibition of TGF-β might reverse the immunosuppressive status on immune cells and restore NK cell mediated anticancer immune responses by upregulation of NKG2DLs in cancer cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12865-021-00434-8.
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20
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Low RECK Expression Is Part of the Cervical Carcinogenesis Mechanisms. Cancers (Basel) 2021; 13:cancers13092217. [PMID: 34066355 PMCID: PMC8124470 DOI: 10.3390/cancers13092217] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 12/15/2022] Open
Abstract
Human papillomavirus (HPV)-induced carcinogenesis comprises alterations in the expression and activity of matrix metalloproteinases (MMP) and their regulators. Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK) inhibits the activation of specific metalloproteinases and its expression is frequently lost in human cancers. Here we analyzed the role of RECK in cervical carcinogenesis. Cervical cancer derived cell lines over expressing RECK were used to determine tumor kinetics as well as, cellular, immune and molecular properties in vivo. Besides, we analyzed RECK expression in cervical cancer samples. RECK over expression (RECK+) delayed tumor growth and increased overall survival in vivo. RECK+ tumors displayed an increase in lymphoid-like inflammatory infiltrating cells, reduced number and viability of tumor and endothelial cells and lower collagenase activity. RECK+ tumors exhibited an enrichment of cell adhesion processes both in the mouse model and cervical cancer clinical samples. Finally, we found that lower RECK mRNA levels were associated with cervical lesions progression and worse response to chemotherapy in cervical cancer patients. Altogether, we show that increased RECK expression reduced the tumorigenic potential of HPV-transformed cells both in vitro and in vivo, and that RECK down regulation is a consistent and clinically relevant event in the natural history of cervical cancer.
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21
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Salminen A. Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases. Ageing Res Rev 2021; 67:101280. [PMID: 33581314 DOI: 10.1016/j.arr.2021.101280] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/28/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
Aging is a progressive degenerative process involving a chronic low-grade inflammation and the accumulation of senescent cells. One major issue is to reveal the mechanisms which promote the deposition of pro-inflammatory senescent cells within tissues. The accumulation involves mechanisms which increase cellular senescence as well as those inhibiting the clearance of senescent cells from tissues. It is known that a persistent inflammatory state evokes a compensatory immunosuppression which inhibits pro-inflammatory processes by impairing the functions of effector immune cells, e.g., macrophages, T cells and natural killer (NK) cells. Unfortunately, these cells are indispensable for immune surveillance and the subsequent clearance of senescent cells, i.e., the inflammation-induced counteracting immunosuppression prevents the cleansing of host tissues. Moreover, senescent cells can also repress their own clearance by expressing inhibitors of immune surveillance and releasing the ligands of NKG2D receptors which impair their surveillance by NK and cytotoxic CD8+ T cells. It seems that cellular senescence and immunosuppression establish a feed-forward process which promotes the aging process and age-related diseases. I will examine in detail the immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging. In addition, I will discuss several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases.
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22
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Baugh R, Khalique H, Seymour LW. Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response. Cancers (Basel) 2020; 12:E3827. [PMID: 33352921 PMCID: PMC7766243 DOI: 10.3390/cancers12123827] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8+ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, expression is significantly increased in response to various types of cellular stress, viral infection, and tumour cell transformation. In order to evade immune-mediated cytotoxicity, both pathogenic viruses and cancer cells have evolved various mechanisms of subverting immune defences and preventing NKG2DL expression. Comparisons of the mechanisms employed following virus infection or malignant transformation reveal a pattern of converging evolution at many of the key regulatory steps involved in NKG2DL expression and subsequent immune responses. Exploring ways to target these shared steps in virus- and cancer-mediated immune evasion may provide new mechanistic insights and therapeutic opportunities, for example, using oncolytic virotherapy to re-engage the innate immune system towards cancer cells.
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Affiliation(s)
| | | | - Leonard W. Seymour
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (R.B.); (H.K.)
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23
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Ferretti E, Carlomagno S, Pesce S, Muccio L, Obino V, Greppi M, Solari A, Setti C, Marcenaro E, Della Chiesa M, Sivori S. Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance. Cancers (Basel) 2020; 12:E3705. [PMID: 33321719 PMCID: PMC7763095 DOI: 10.3390/cancers12123705] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/01/2020] [Accepted: 12/07/2020] [Indexed: 12/19/2022] Open
Abstract
Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands. In this review, we summarize the role of the main non-HLA-specific activating NK receptors, NCRs, NKG2D and DNAM-1, in controlling tumor growth and metastatic spread in solid malignancies affecting the gastrointestinal tract with high incidence in the world population, i.e., pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and gastric cancer (GC), also describing the phenotypic and functional alterations induced on NK cells by their tumor microenvironment.
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Affiliation(s)
- Elisa Ferretti
- Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, 16132 Genoa, Italy;
| | - Simona Carlomagno
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Silvia Pesce
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Letizia Muccio
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Valentina Obino
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Marco Greppi
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Agnese Solari
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Chiara Setti
- Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, 16132 Genoa, Italy; (S.C.); (S.P.); (L.M.); (V.O.); (M.G.); (A.S.); (C.S.)
| | - Emanuela Marcenaro
- Dipartimento di Medicina Sperimentale (DIMES) and Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, 16132 Genoa, Italy;
| | - Mariella Della Chiesa
- Dipartimento di Medicina Sperimentale (DIMES) and Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, 16132 Genoa, Italy;
| | - Simona Sivori
- Dipartimento di Medicina Sperimentale (DIMES) and Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, 16132 Genoa, Italy;
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24
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Barillari G. The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process. Int J Mol Sci 2020; 21:ijms21124526. [PMID: 32630531 PMCID: PMC7350258 DOI: 10.3390/ijms21124526] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/20/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient's health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.
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Affiliation(s)
- Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 1 via Montpellier, 00133 Rome, Italy
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25
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Xu P, Sun Y, Song Y, Jiao J, Shen B, Li W, Jiang C, Li Y, Zhang X, Yu J, Fu L, Guo X. ATM kinase regulates tumor immunoreactions in lymphocyte-predominant breast cancer through modulation of NKG2D ligand and TNF cytokines on tumor cells. Med Mol Morphol 2020; 53:210-220. [PMID: 32067111 DOI: 10.1007/s00795-020-00247-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/03/2020] [Indexed: 11/26/2022]
Abstract
To explore impact of Ataxia telangiectasia mutated (ATM) kinase on immunoreactions in lymphocyte-predominant breast cancer (LPBC), particularly its role in triple negative breast cancer (TNBC), 194 cases of LPBC were identified with pertinent clinical information retrieved. The expressions of ATM, activated ATM (P-ATM), Fas ligand (FASL), tumor necrosis factor-related apoptosis-induced ligand (TRAIL), major histocompatibility complex class I chain-related protein A (MICA), CD8, and Forkhead box P3 (FOXP3) were assessed by immunohistochemically. We found that ATM expressed on tumor cells was correlated with upregulated expression of P-ATM and MICA (P < 0.05), down-regulated expression of FASL and TRAIL (P < 0.01), and decreased Ki-67 tumor labeling (P < 0.05). However, within the TNBC group, only a negative correlation with FASL expression was found (P = 0.001). ATM and MICA expressions were significantly down -regulated in TNBC (P < 0.01) compared to non-TNBC, while TRAIL was significantly upregulated (P < 0.01). Tregs were increased in TNBC (P < 0.05), with CD8 + TILs decreased (P < 0.01). Ki-67 index was higher in TNBC than in non-TNBC (P < 0.01). ATM may play an important role in immunoreaction of LPBC, probably through upregulation of MICA and down-regulation of FASL and TRAIL. The down-regulated ATM expression in TNBC might be responsible for impaired tumor immunoactivity, rapid tumor growth, and aggressive clinical course.
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Affiliation(s)
- Peng Xu
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yuanyuan Sun
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yuanming Song
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Jiao Jiao
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Beibei Shen
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Weidong Li
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Chengying Jiang
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yaqing Li
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Xinmin Zhang
- Department of Pathology, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Li Fu
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Xiaojing Guo
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China.
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26
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Rossi GR, Trindade ES, Souza-Fonseca-Guimaraes F. Tumor Microenvironment-Associated Extracellular Matrix Components Regulate NK Cell Function. Front Immunol 2020; 11:73. [PMID: 32063906 PMCID: PMC7000552 DOI: 10.3389/fimmu.2020.00073] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
The tumor microenvironment (TME) is composed of multiple infiltrating host cells (e.g., endothelial cells, fibroblasts, lymphocytes, and myeloid cells), extracellular matrix, and various secreted or cell membrane-presented molecules. Group 1 innate lymphoid cells (ILCs), which includes natural killer (NK) cells and ILC1, contribute to protecting the host against cancer and infection. Both subsets are able to quickly produce cytokines such as interferon gamma (IFN-γ), chemokines, and other growth factors in response to activating signals. However, the TME provides many molecules that can prevent the potential effector function of these cells, thereby protecting the tumor. For example, TME-derived tumor growth factor (TGF)-β and associated members of the superfamily downregulate NK cell cytotoxicity, cytokine secretion, metabolism, proliferation, and induce effector NK cells to upregulate ILC1-like characteristics. In concert, a family of carbohydrate-binding proteins called galectins, which can be produced by different cells composing the TME, can downregulate NK cell function. Matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) are also enzymes that can remodel the extracellular matrix and shred receptors from the tumor cell surface, impairing the activation of NK cells and leading to less effective effector functions. Gaining a better understanding of the characteristics of the TME and its associated factors, such as infiltrating cells and extracellular matrix, could lead to tailoring of new personalized immunotherapy approaches. This review provides an overview of our current knowledge on the impact of the TME and extracellular matrix-associated components on differentiation, impairment, and function of NK cells.
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Affiliation(s)
| | - Edvaldo S Trindade
- Cellular Biology Department, Federal University of Paraná, Curitiba, Brazil
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27
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Lim KS, Mimura K, Kua LF, Shiraishi K, Kono K. Implication of Highly Cytotoxic Natural Killer Cells for Esophageal Squamous Cell Carcinoma Treatment. J Immunother 2019; 41:261-273. [PMID: 29683892 DOI: 10.1097/cji.0000000000000227] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is an aggressive upper gastrointestinal cancer and effective treatments are limited. Previous studies reported that natural killer (NK) cells expanded by coculturing with K562-mb15-41BBL feeder cells, a genetically modified K562 leukemia cell line that expresses membrane-bound interleukin (IL)-15 and 41BBL ligand, were highly proliferative and highly cytotoxic. Here, we investigated the potential of expanded NK cells for ESCC treatment. We analyzed both genetic and surface expression levels of NKG2D ligands (NKG2DLs) in ESCC using publicly available microarray data sets and ESCC cell lines. The cytotoxicity of resting and of IL-2-activated NK cells against ESCC cell lines was compared with that of expanded NK cells. We then also investigated the effect of epithelial mesenchymal transition (EMT) inducers, GSK3β inhibitor and epidermal growth factor, on NKG2DLs expressions. As a result, MICA and MICB were significantly overexpressed in ESCC compared with adjacent normal tissues and surface NKG2DLs were expressed in ESCC cell lines. Expanded NK cells were much potent than IL-2-activated and resting NK cells against ESCC cell lines. Blocking of NKG2D with anti-NKG2D monoclonal antibody dampened expanded NK cell cytotoxicity, suggesting that the NKG2DLs-NKG2D interaction is crucial for NK cells to eliminate ESCC cells. EMT inducers concurrently induced EMT and NKG2DLs expression in ESCC cell lines rendering transitioned cells more sensitive to expanded NK cells. In conclusion, expanded NK cells were highly cytotoxic against NKG2DLs-expressing ESCC cells, particularly the EMT phenotype. These results provide a strong rationale for clinical use of these NK cells in ESCC patients.
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Affiliation(s)
| | - Kosaku Mimura
- Departments of Gastrointestinal Tract Surgery.,Advanced Cancer Immunotherapy.,Progressive DOHaD Research
| | - Ley-Fang Kua
- Department of Hematology-Oncology, National University of Singapore, Singapore
| | - Kensuke Shiraishi
- Department of Surgery, Fujikawa Hospital, Kyonan Medical Center, Kajikazawa Fujikawa-cho, Minamikoman-gun, Yamanashi, Japan
| | - Koji Kono
- Departments of Gastrointestinal Tract Surgery.,Advanced Cancer Immunotherapy.,Organ Regulatory Surgery, Fukushima Medical University, Fukushima City, Fukushima
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Frazao A, Rethacker L, Messaoudene M, Avril MF, Toubert A, Dulphy N, Caignard A. NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment. Front Immunol 2019; 10:661. [PMID: 30984204 PMCID: PMC6449444 DOI: 10.3389/fimmu.2019.00661] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 03/11/2019] [Indexed: 12/18/2022] Open
Abstract
The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach.
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Affiliation(s)
- Alexandra Frazao
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France
| | - Louise Rethacker
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France
| | - Meriem Messaoudene
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.,U1015 INSERM-CIC, Institut Gustave Roussy, Villejuif, France
| | - Marie-Françoise Avril
- Assistance Publique-Hôpitaux de Paris, Department of Dermatology, Hospital Cochin, University Paris Descartes, Paris, France.,Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France
| | - Antoine Toubert
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.,Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Department of Immunology and Histocompatibility, Paris, France
| | - Nicolas Dulphy
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.,Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Department of Immunology and Histocompatibility, Paris, France
| | - Anne Caignard
- INSERMU1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France
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29
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The Relationship Between Phospho-p38, Matrix Metalloproteinase 9, and Major Histocompatibility Complex Class I Chain-Related Molecule A Expression in Pituitary Adenomas Demonstrates a New Mechanism of Pituitary Adenoma Immune Escape. World Neurosurg 2018; 123:e116-e124. [PMID: 30458325 DOI: 10.1016/j.wneu.2018.11.077] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 11/21/2022]
Abstract
BACKGROUND The major histocompatibility complex class I chain-related molecule A (MICA) is one of the natural killer group 2D ligands. Soluble major histocompatibility complex class I chain-related molecule A (sMICA) mediates tumor immune escape, but the mechanism is not fully understood. In this study, we examined the expression of phospho-p38, matrix metalloproteinase 9 (MMP-9), and MICA and their relationships among each other in pituitary adenoma tissues to provide a histologic basis for the mechanism of pituitary adenoma immune escape. METHODS We applied immunohistochemistry, real-time quantitative reverse-transcriptase polymerase chain reaction, and Western blot to detect phospho-p38, MMP-9, and MICA expression at the mRNA and protein levels in pituitary adenoma tissues. Enzyme-linked immunosorbent assay was used to examine the expression levels of MMP-9 and sMICA in peripheral blood serum from patients with pituitary adenoma. RESULTS We found that p38, MICA, and MMP-9 mRNA levels were greater in pituitary adenomas than in normal tissues. The phospho-p38, MMP-9, and MICA proteins were overexpressed in pituitary adenomas, and the expression of MMP-9 and MICA were positively correlated with the expression of phospho-p38. In addition, the serum levels of sMICA and MMP-9 proteins in pituitary adenoma patients were significantly greater than those in normal controls. CONCLUSIONS These findings suggest that activation of the p38/mitogen-activated protein kinase pathway may increase MICA expression and induce MMP-9 expression. MMP-9 is involved in the shedding of sMICA from MICA to promote tumor immune escape. Furthermore, p38/mitogen-activated protein kinase could potentially represent a novel target for inhibiting pituitary adenoma immune escape.
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30
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Schmiedel D, Mandelboim O. NKG2D Ligands-Critical Targets for Cancer Immune Escape and Therapy. Front Immunol 2018; 9:2040. [PMID: 30254634 PMCID: PMC6141707 DOI: 10.3389/fimmu.2018.02040] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/20/2018] [Indexed: 12/21/2022] Open
Abstract
DNA damage, oncogene activation and excessive proliferation, chromatin modulations or oxidative stress are all important hallmarks of cancer. Interestingly, all of these abnormalities also induce a cellular stress response. By upregulating “stress-induced ligands,” damaged or transformed cells can be recognized by immune cells and cleared. The human genome encodes eight functional “stress-induced ligands”: MICA, MICB, and ULBP1-6. All of them are recognized by a single receptor, NKG2D, which is expressed on natural killer (NK) cells, cytotoxic T cells and other T cell subsets. The NKG2D ligand/NKG2D-axis is well-recognized as an important mediator of anti-tumor activity; however, patient data about the role of NKG2D ligands in immune surveillance and escape appears conflicting. As these ligands are often actively transcribed, tumor cells are urged to manipulate the expression of these ligands on post-transcriptional or post-translational level. Although our knowledge on the regulation of NKG2D ligand expression remains fragmentary, research of the past years revealed multiple cellular mechanisms that are adopted by tumor cells to reduce the expression of “stress-induced ligands” and therefore escape immune recognition. Here, we review the post-transcriptional and post-translational mechanisms by which NKG2D ligands are modulated in cancer cells and their impact on patient prognosis.We discuss controversies and approaches to apply our understanding of the NKG2D ligand/NKG2D-axis for cancer therapy.
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Affiliation(s)
- Dominik Schmiedel
- The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Ofer Mandelboim
- The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel
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Abstract
Natural killer (NK) cells are cytotoxic lymphocytes that recognize tumor cells or stressed cells through 'missing-self' signals, such as altered or absent expression of MHC class I molecules. The function of NK cells is regulated by the activation or inhibition of receptors present on their surface. The activation of NK cells results in cytotoxic activity on target cells through release of toxic granules and inflammatory cytokines. However, NK cells infiltrating tumors have been frequently shown to exhibit a skewed phenotype that includes decreased antitumor activity and enhanced protumor activities, such as angiogenesis and metastasis. In fact, many studies have reported that tumor microenvironments induce a protumor phenotype in NK cells. Here, we review the biological properties of NK cells in the context of tumorigenesis and tumor progression, with a specific focus on the interactions between NK cells and critical tumor microenvironments, such as epithelial-to-mesenchymal transition, matrix metalloproteinases, and tumor-associated chronic inflammation in tumor metastasis.
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32
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Ziani L, Safta-Saadoun TB, Gourbeix J, Cavalcanti A, Robert C, Favre G, Chouaib S, Thiery J. Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion. Oncotarget 2017; 8:19780-19794. [PMID: 28423623 PMCID: PMC5386721 DOI: 10.18632/oncotarget.15540] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 01/16/2017] [Indexed: 11/25/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) play a central role in the complex process of tumor-stroma interaction and promote tumor growth. Emerging evidences also suggest that these fibroblasts are involved in the alteration of the anti-tumor immune response by impacting several immune cell populations, especially through their secretion of pro-inflammatory and immunosuppressive factors in the tumor microenvironment. However, the underlying immuno-modulating mechanisms triggered by these fibroblasts are still only partially defined. In this study, we provide evidence that melanoma-associated fibroblasts decrease the susceptibility of melanoma tumor cells to NK-mediated lysis through the secretion of active matrix metalloproteinases. This secretion reduces the expression of the two NKG2D ligands, MICA/B, at the surface of tumor cells and consequently decreases the NKG2D-dependent cytotoxic activity of NK cells against melanoma tumor cells. Together, our data demonstrate that the modification of tumor cell susceptibility to killer cells is an important determinant of the anti-tumor immune response alteration triggered by CAFs.
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Affiliation(s)
- Linda Ziani
- INSERM, UMR 1186, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France
| | - Thouraya Ben Safta-Saadoun
- INSERM, UMR 1186, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France
| | - Johanne Gourbeix
- INSERM, UMR 1186, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France
| | - Andrea Cavalcanti
- Department of General Surgery, Gustave Roussy Cancer Campus, Villejuif, France
| | - Caroline Robert
- Gustave Roussy Cancer Campus, Villejuif, France.,University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France.,INSERM, UMR 981, Villejuif, France.,Dermatology Service, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | | | - Salem Chouaib
- INSERM, UMR 1186, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France
| | - Jerome Thiery
- INSERM, UMR 1186, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France
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