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Li G, Li S, Jiang Y, Chen T, An Z. Unleashing the Power of immune Checkpoints: A new strategy for enhancing Treg cells depletion to boost antitumor immunity. Int Immunopharmacol 2025; 147:113952. [PMID: 39764997 DOI: 10.1016/j.intimp.2024.113952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 12/22/2024] [Accepted: 12/24/2024] [Indexed: 01/29/2025]
Abstract
Regulatory T (Treg) cells, immunosuppressive CD4+ T cells, can impede anti-tumor immunity, complicating cancer treatment. Since their discovery, numerous studies have been dedicated to understand Treg cell biology, with a focus on checkpoint pathways' role in their generation and function. Immune checkpoints, such as PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, and OX40, are pivotal in controlling Treg cell expansion and activity in the tumor microenvironment (TME), affecting their ability to suppress immune responses. This review examines the complex relationship between these checkpoints and Tregs in the TME, and how they influence tumor immunity. We also discuss the therapeutic potential of targeting these checkpoints to enhance anti-tumor immunity, including the use of immune checkpoint blockade (ICB) therapies and novel approaches such as CCR8-targeted therapies. Understanding the interaction between immune checkpoints and Treg cells can lead to more effective immunotherapeutic strategies, such as combining CCR8-targeted therapies with immune checkpoint inhibitors, to improve patient outcomes in cancer treatment.
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Affiliation(s)
- Guoxin Li
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China; Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Siqi Li
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Yilin Jiang
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Tao Chen
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhengwen An
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China; Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China.
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Liao JB, Jejurikar NS, Hitchcock-Bernhardt KM, Gwin WR, Reichow JL, Dang Y, Childs JS, Coveler AL, Swensen RE, Goff BA, Disis ML, Salazar LG. Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer. Gynecol Oncol 2024; 191:74-79. [PMID: 39362046 PMCID: PMC11637896 DOI: 10.1016/j.ygyno.2024.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
BACKGROUND Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. PATIENTS AND METHODS A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. RESULTS The maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1-2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. CONCLUSIONS Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov # NCT00357448.
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Affiliation(s)
- John B Liao
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America.
| | - Nikita S Jejurikar
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Katie M Hitchcock-Bernhardt
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - William R Gwin
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Jessica L Reichow
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Yushe Dang
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Jennifer S Childs
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Andrew L Coveler
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Ron E Swensen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America; Valley Medical Center, 400 South 43(rd) Street, Renton, WA 98055, United States of America
| | - Barbara A Goff
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America
| | - Mary L Disis
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Lupe G Salazar
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
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Chang X, Miao J. Role of TIM-3 in ovarian cancer: the forsaken cop or a new noble. Front Immunol 2024; 15:1407403. [PMID: 39206199 PMCID: PMC11350557 DOI: 10.3389/fimmu.2024.1407403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
T cell immunoglobulin and mucin domain-3 (TIM-3), a crucial immune checkpoint following PD1 and CTLA4, is widely found in several immune cells. Nonetheless, its performance in recent clinical trials appears disappointing. Ovarian cancer (OC), a malignant tumor with a high mortality rate in gynecology, faces significant hurdles in immunotherapy. The broad presence of TIM-3 offers a new opportunity for immunotherapy in OC. This study reviews the role of TIM-3 in OC and assesses its potential as a target for immunotherapy. The regulatory effects of TIM-3 on the immune microenvironment in OC are discussed, with a focus on preclinical studies that demonstrate TIM-3's modulation of various immune cells in OC. Additionally, the potential therapeutic advantages and challenges of targeting TIM-3 in OC are examined.
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Affiliation(s)
| | - Jinwei Miao
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
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Dawidowicz M, Kot A, Mielcarska S, Psykała K, Kula A, Waniczek D, Świętochowska E. B7H4 Role in Solid Cancers: A Review of the Literature. Cancers (Basel) 2024; 16:2519. [PMID: 39061159 PMCID: PMC11275172 DOI: 10.3390/cancers16142519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/27/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Anti-cancer immunotherapies entirely changed the therapeutic approach to oncological patients. However, despite the undeniable success of anti-PD-1, PD-L1, and CTLA-4 antibody treatments, their effectiveness is limited either by certain types of malignancies or by the arising problem of cancer resistance. B7H4 (aliases B7x, B7H4, B7S1, VTCN1) is a member of a B7 immune checkpoint family with a distinct expression pattern from classical immune checkpoint pathways. The growing amount of research results seem to support the thesis that B7H4 might be a very potent therapeutic target. B7H4 was demonstrated to promote tumour progression in immune "cold" tumours by promoting migration, proliferation of tumour cells, and cancer stem cell persistence. B7H4 suppresses T cell effector functions, including inflammatory cytokine production, cytolytic activity, proliferation of T cells, and promoting the polarisation of naïve CD4 T cells into induced Tregs. This review aimed to summarise the available information about B7H4, focusing in particular on clinical implications, immunological mechanisms, potential strategies for malignancy treatment, and ongoing clinical trials.
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Affiliation(s)
- Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Katarzyna Psykała
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
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5
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Meza-Perez S, Liu M, Silva-Sanchez A, Morrow CD, Eipers PG, Lefkowitz EJ, Ptacek T, Scharer CD, Rosenberg AF, Hill DD, Arend RC, Gray MJ, Randall TD. Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine. Cell Host Microbe 2024; 32:1177-1191.e7. [PMID: 38942027 PMCID: PMC11245731 DOI: 10.1016/j.chom.2024.06.003] [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: 11/16/2023] [Revised: 04/19/2024] [Accepted: 06/04/2024] [Indexed: 06/30/2024]
Abstract
Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.
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Affiliation(s)
- Selene Meza-Perez
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Mingyong Liu
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Aaron Silva-Sanchez
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Casey D Morrow
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Peter G Eipers
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Elliot J Lefkowitz
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Travis Ptacek
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Christopher D Scharer
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Alexander F Rosenberg
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Dave D Hill
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Rebecca C Arend
- Department of Obstetrics and Gynecology, Division of Gynecological Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Michael J Gray
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Troy D Randall
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Zhao L, Chen X, Wu H, He Q, Ding L, Yang B. Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer. Biochem Pharmacol 2023; 215:115724. [PMID: 37524205 DOI: 10.1016/j.bcp.2023.115724] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/02/2023]
Abstract
Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies.
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Affiliation(s)
- Lin Zhao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xi Chen
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Honghai Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China
| | - Ling Ding
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
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Alwosaibai K, Aalmri S, Mashhour M, Ghandorah S, Alshangiti A, Azam F, Selwi W, Gharaibeh L, Alatawi Y, Alruwaii Z, Alsaab HO. PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers. BMC Cancer 2023; 23:13. [PMID: 36604635 PMCID: PMC9814309 DOI: 10.1186/s12885-022-10404-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 12/05/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors, including PD-L1 (programmed death ligand-1) inhibitors have well documented anticancer therapeutic effect in most types of cancers but its use in the treatment of ovarian cancer is not yet proven. The aim of our study is to explore the predictive biomarkers in ovarian cancer and its association with the outcomes. We have investigated the role of PD-L1 expressions in the tumor microenvironment cells including immune cells and cancer stem cells in different types of ovarian cancer. METHODS A total of 119 surgical archived ovarian cancer samples were collected from the pathology department at King Fahad Specialist Hospital, Dammam, Saudi Arabia that included serous carcinomas, clear cell carcinomas, mucinous carcinomas, endometrioid carcinomas, and granulosa cell tumors. Immunohistochemistry (IHC) staining was performed using (i) PD-L1 antibodies to detect PD-L1 expressions; (ii) CD8 and CD4 to detect Tumor Infiltrating Lymphocytes (TILs); and (iii) CD44, LGR5, and ALDH2 to detect stem cell markers. The clinicopathological data were collected from patients' medical record to investigate the association with PD-L1, TILs, and stem cells expressions. RESULTS We report high PD-L1 expressions in 47.8% of ovarian cancer samples. PD-L1 expressions were detected in different types of epithelial ovarian cancer and were not associated with poor prognosis of ovarian cancer. However, determining the expression levels of TILs in the ovarian cancer tissues found that 81% (n = 97) of ovarian cancer samples have TILs that express both of CD8 and CD4 and significantly associated with high PD-L1 expressions. Interestingly, we have found that ovarian cancer tissues with high expressions of PD-L1 were associated with high expressions of stem cells expressing CD44 and LGR5. CONCLUSIONS PD-L1 is highly expressed in the serous type of ovarian carcinomas and the overall expression of PD-L1 is not associated with poor survival rate. Furthermore, PD-L1 expressions are strongly associated with TILs and stem cell markers in ovarian cancer. Inhibiting the PD-L1 using immune checkpoint inhibitors might downregulate stem cell population that known to be associated with cancer recurrence.
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Affiliation(s)
- Kholoud Alwosaibai
- grid.415280.a0000 0004 0402 3867Research Center, Biomedical Research Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Salmah Aalmri
- grid.415280.a0000 0004 0402 3867Research Center, Biomedical Research Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Miral Mashhour
- grid.415280.a0000 0004 0402 3867Department of Pathology and Lab Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Salim Ghandorah
- grid.415280.a0000 0004 0402 3867Department of Pathology and Lab Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Abdulraheem Alshangiti
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Faisal Azam
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Waleed Selwi
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Lubna Gharaibeh
- grid.116345.40000000406441915Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Yasser Alatawi
- grid.440760.10000 0004 0419 5685Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Zainab Alruwaii
- Department of Anatomic Pathology, Dammam Regional Laboratory and Blood Bank, Dammam, Saudi Arabia
| | - Hashem O. Alsaab
- grid.412895.30000 0004 0419 5255Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O BOX 11099, Taif, Saudi Arabia
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Kozłowski M, Borzyszkowska D, Cymbaluk-Płoska A. The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer. Biomedicines 2022; 10:2826. [PMID: 36359346 PMCID: PMC9687228 DOI: 10.3390/biomedicines10112826] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/30/2022] [Accepted: 11/03/2022] [Indexed: 08/11/2023] Open
Abstract
Ovarian cancer has the highest mortality rate among gynecologic malignancies. The main treatment options are surgical removal of the tumor and chemotherapy. Cancer treatment has been revolutionized by immunotherapy, which has developed explosively over the past two decades. Clinical anticancer strategies used in immunotherapy include therapies based on the inhibition of PD-1, PD-L1 or CTLA-4. Despite encouraging results, a large proportion of cancer patients are resistant to these therapies or eventually develop resistance. It is important to perform research that will focus on immunotherapy based on other immune checkpoint inhibitors. The aim of the review was to analyze studies considering the expression of TIM-3 and LAG-3 in the ovarian cancer microenvironment and considering immunotherapy for ovarian cancer that includes antibodies directed against TIM-3 and LAG-3. As the data showed, the expression of the described immune checkpoints was shown in different ways. Higher TIM-3 expression was associated with a more advanced tumor stage. Both TIM-3 and LAG-3 were co-expressed with PD-1 in a large proportion of studies. The effect of LAG-3 expression on progression-free survival and/or overall survival is inconclusive and certainly requires further study. Co-expression of immune checkpoints prompts combination therapies using anti-LAG-3 or anti-TIM-3. Research on immune checkpoints, especially TIM-3 and LAG-3, should be further developed.
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10
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Immune Tumor Microenvironment in Ovarian Cancer Ascites. Int J Mol Sci 2022; 23:ijms231810692. [PMID: 36142615 PMCID: PMC9504085 DOI: 10.3390/ijms231810692] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/26/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.
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Hair J, Robinson MJ, Wilkinson RW, Dovedi SJ. Deep phenotyping of surface stimulatory and inhibitory co-receptors on cancer-resident T and NK cells reveals cell subsets within the tumor-reactive CTL population that are uniquely defined by NKG2A expression. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2022; 27:95-106. [PMID: 35058180 DOI: 10.1016/j.slasd.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The field of Immuno-Oncology (IO) is evolving to utilise novel antibody backbones that can co-target multiple cell-surface stimulatory and inhibitory co-receptors (SICR). This approach necessitates a better understanding of SICR co-expression at the single-cell level on IO-relevant tumor-infiltrating leukocyte (TIL) cell types such as T and natural killer (NK) cells. Using high-dimensional flow cytometry we established a comprehensive SICR profile for tumor-resident T and NK cells across a range of human solid tumors where there is a clear need for improved immunotherapeutic intervention. Leveraging the power of our large flow panel, we performed deep-phenotyping of the critical CD8+CD39+ Cytotoxic T Lymphocyte (CTL) population that is enriched for tumor-reactive cytotoxic cells, revealing subsets that are differentiated by their SICR profile, including three that are uniquely defined by NKG2A expression. This study establishes a comprehensive SICR phenotype for human TIL T and NK cells, providing insights to guide the design and application of the next generation of IO molecules.
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Affiliation(s)
- James Hair
- Early Oncology R&D, AstraZeneca, Granta Park, Cambridge, UK.
| | | | | | - Simon J Dovedi
- Early Oncology R&D, AstraZeneca, Granta Park, Cambridge, UK
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12
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霍 叶, 王 月, 安 娜, 杜 雪. [TIM-3 gene is highly expressed in ephithelial ovarian cancer to promote proliferation and migration of ovarian cancer cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:190-200. [PMID: 35365442 PMCID: PMC8983363 DOI: 10.12122/j.issn.1673-4254.2022.02.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To analyze the expression of immunoglobulin mucin molecule 3 (TIM-3) in epithelial ovarian cancer (EOC) and the effects of TIM-3 knockdown and overexpression on proliferation and migration of ovarian cancer cells. METHODS We analyzed TIM-3 expression in EOC and normal ovarian tissues using GEPIA database. We also detected TIM-3 expression levels in 82 surgical specimens of EOC and 18 specimens of normal ovarian tissues using immunohistochemistry, and analyzed the correlation of TIM-3 expression with clinicopathological parameters and survival outcomes of the patients. The expression of TIM-3 and Wnt1 mRNA in the tissues were detected using qRT-PCR. We constructed SKOV3 cell models of TIM-3 knockdown and overexpression and examined the changes in proliferation, apoptosis, migration and invasion of the cells using MTT assay, Annexin V-FITC/PI staining, scratch test and Transwell assay. The activity of Wnt/β-catenin pathway in the transfected was detected using dual luciferase reporter assay, and the mRNA levels of TCF-7, TCCFL-2 and CD44 were detected using qPCR. The protein expressions of MMP-9, CD44, Wnt1, β-catenin and E-cad in the transfected cells were detected with Western blotting. RESULTS The positive expression rate of TIM-3 was significantly higher in EOC tissues than in normal ovarian tissues (P < 0.05). The expression of TIM-3 was significantly correlated with FIGO stage, histological differentiation and lymph node metastasis, and was positively correlated with Wnt1 level (P < 0.05). In SKOV3 cells, TIM-3 knockdown significantly lowered the activity of Wnt/ β-catenin pathway, inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. TIM-3 knockdown significantly down-regulated the mRNA levels of TCF-7, TCFL-2 and CD44 and the protein levels of MMP-9, CD44, Wnt1 and β-catenin, and significantly up-regulated the expression level of E-cad (P < 0.05). Overexpression of TIM-3 caused opposite effects in SKOV3 cells. CONCLUSION TIM-3 is highly expressed in EOC tissue to promote malignant behaviors of the tumor cells possibly by activating the Wnt/β-catenin signal pathway.
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Affiliation(s)
- 叶琳 霍
- 天津医科大学总医院妇科，天津 300000Department of Gynecology, General Hospital of Tianjin Medical University, Tianjin 300000, China
- 河北省保定市第一医院妇科，河北 保定 071000Department of Gynecology, Baoding First Hospital, Baoding 071000, China
| | - 月 王
- 河北大学附属医院肿瘤内科，河北 保定 071000Department of Oncology, Affiliated Hospital of Hebei University, Baoding 071000, China
| | - 娜 安
- 河北大学附属医院肿瘤内科，河北 保定 071000Department of Oncology, Affiliated Hospital of Hebei University, Baoding 071000, China
| | - 雪 杜
- 天津医科大学总医院妇科，天津 300000Department of Gynecology, General Hospital of Tianjin Medical University, Tianjin 300000, China
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13
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Hatzioannou A, Boumpas A, Papadopoulou M, Papafragkos I, Varveri A, Alissafi T, Verginis P. Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle. Front Immunol 2021; 12:731947. [PMID: 34539668 PMCID: PMC8446642 DOI: 10.3389/fimmu.2021.731947] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 01/08/2023] Open
Abstract
Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.
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Affiliation(s)
- Aikaterini Hatzioannou
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Athina Boumpas
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Miranta Papadopoulou
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Iosif Papafragkos
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Athina Varveri
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Themis Alissafi
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Panayotis Verginis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
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14
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Leary A, Tan D, Ledermann J. Immune checkpoint inhibitors in ovarian cancer: where do we stand? Ther Adv Med Oncol 2021; 13:17588359211039899. [PMID: 34422119 PMCID: PMC8377306 DOI: 10.1177/17588359211039899] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/29/2021] [Indexed: 11/16/2022] Open
Abstract
Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.
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Affiliation(s)
- Alexandra Leary
- Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France, Université Paris-Saclay, INSERM U981, Villejuif, France
| | - David Tan
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Cancer Science Institute, National University of Singapore, Singapore
| | - Jonathan Ledermann
- UCL Cancer Institute, Cancer Research UK and UCL Trials Centre, London, UK
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15
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Lu X. Structure and functions of T-cell immunoglobulin-domain and mucin- domain protein 3 in cancer. Curr Med Chem 2021; 29:1851-1865. [PMID: 34365943 DOI: 10.2174/0929867328666210806120904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling. METHODS This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types, and the rationale for TIM-3-targeted cancer immunotherapy. RESULTS TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models. CONCLUSION TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.
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Affiliation(s)
- Xinjie Lu
- The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London, SW3 6LR. United Kingdom
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16
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Niu N, Shen W, Zhong Y, Bast RC, Jazaeri A, Sood AK, Liu J. Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas. Hum Pathol 2021; 113:20-27. [PMID: 33887301 DOI: 10.1016/j.humpath.2021.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/27/2022]
Abstract
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
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Affiliation(s)
- Na Niu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Weiwei Shen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Oncology, Tangdu Hospital, Xi'an, Shaanxi, 710038, China
| | - Yanping Zhong
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Robert C Bast
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Amir Jazaeri
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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17
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Zhong W, Liu X, Zhu Z, Li Q, Li K. High levels of Tim-3 +Foxp3 +Treg cells in the tumor microenvironment is a prognostic indicator of poor survival of diffuse large B cell lymphoma patients. Int Immunopharmacol 2021; 96:107662. [PMID: 33864956 DOI: 10.1016/j.intimp.2021.107662] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 12/27/2022]
Abstract
Foxp3+Treg cells display phenotypic and functional heterogeneity, which express high levels of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) in the tumor microenvironment (TME) of colorectal and lung cancer. High abundance of Tim-3+Foxp3+Treg (TFT) cells are associated with poor prognosis in these patients. However, the expression patterns and roles of TFT cells in TME of diffuse large B cell lymphoma (DLBCL) remain to be established. Double immunofluorescence and flow cytometry analyses were employed to investigate TFT cell enrichment in paraffin-embedded fresh tumor tissues from patients with DLBCL. Spearman's or Pearson's correlation and Kaplan-Meier survival analyses were further applied to decide the prognostic value of TFT cell levels in DLBCL. The IL-10-secreting function of TFT cells in vitro was examined via flow cytometry and ELISA. Our results showed for the first time that TFT cells are highly enriched in TME of DLBCL patients and associated with predictions of poor prognoses. TFT cell-induced secretion of IL-10 in the TME was suppressed by an anti-Tim-3 antibody in vitro. In conclusion, high abundance of TFT cells in the TME is predictive of poor outcomes of DLBCL. TFT cells promote DLBCL development partly by secreting IL-10 in the TME. Anti-Tim-3 antibodies (that block IL-10 secretion) may present an effective therapeutic agent for DLBCL.
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Affiliation(s)
- Weijie Zhong
- Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Xiudan Liu
- Department of Medical Ultrasound, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Zhigang Zhu
- Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Qingshan Li
- Department of Hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, China.
| | - Kangbao Li
- Department of Geriatrics, Gastroenterology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China.
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18
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Sarkar T, Dhar S, Sa G. Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape. CURRENT RESEARCH IN IMMUNOLOGY 2021; 2:132-141. [PMID: 35492399 PMCID: PMC9040151 DOI: 10.1016/j.crimmu.2021.08.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/16/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.
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19
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Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1330:75-94. [PMID: 34339031 DOI: 10.1007/978-3-030-73359-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The majority of ovarian cancer patients present clinically with wide-spread metastases throughout the peritoneal cavity, metastasizing to the mesothelium-lined peritoneum and visceral adipose depots within the abdomen. This unique metastatic tumor microenvironment is comprised of multiple cell types, including mesothelial cells, fibroblasts, adipocytes, macrophages, neutrophils, and T lymphocytes. Modeling advancements, including complex 3D systems and organoids, coupled with 2D cocultures, in vivo mouse models, and ex vivo human tissue cultures have greatly enhanced our understanding of the tumor-stroma interactions that are required for successful metastasis of ovarian cancer cells. However, advanced multifaceted model systems that incorporate frequency and spatial distribution of all cell types present in the tumor microenvironment of ovarian cancer are needed to enhance our knowledge of ovarian cancer biology in order to identify methods for preventing and treating metastatic disease. This review highlights the utility of recently developed modeling approaches, summarizes some of the resulting progress using these techniques, and suggests how these strategies may be implemented to elucidate signaling processes among cell types of the tumor microenvironment that promote ovarian cancer metastasis.
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20
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Galgani M, Bruzzaniti S, La Rocca C, Micillo T, de Candia P, Bifulco M, Matarese G. Immunometabolism of regulatory T cells in cancer. Mol Aspects Med 2020; 77:100936. [PMID: 33250195 DOI: 10.1016/j.mam.2020.100936] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/19/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023]
Abstract
Regulatory T (Treg) cells are known to orchestrate the regulatory mechanisms aimed at suppressing pathological auto-reactive immune responses and are thus key in ensuring the maintenance of immune homeostasis. On the other hand, the presence of Treg cells with enhanced suppressive capability in a plethora of human cancers represents a major obstacle to an effective anti-cancer immune response. A relevant research effort has thus been dedicated to comprehend Treg cell biology, leading to a continuously refining characterization of their phenotype and function and unveiling the central role of metabolism in ensuring Treg cell fitness in cancer. Here we focus on how the peculiar biochemical characteristics of the tumor microenvironment actually support Treg cell metabolic activation and favor their selective survival and proliferation. Moreover, we examine the key metabolic pathways that may become useful targets of novel treatments directed at hampering tumor resident Treg cell proficiency, thus representing the next research frontier in cancer immunotherapy.
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Affiliation(s)
- Mario Galgani
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy; Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy
| | - Sara Bruzzaniti
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy; Dipartimento di Biologia, Università Degli Studi di Napoli "Federico II", 80126, Napoli, Italy
| | - Claudia La Rocca
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy
| | - Teresa Micillo
- Unità di Neuroimmunologia, Fondazione Santa Lucia IRCCS, 00179, Roma, Italy
| | | | - Maurizio Bifulco
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy
| | - Giuseppe Matarese
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy; Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy.
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21
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James NE, Woodman M, DiSilvestro PA, Ribeiro JR. The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer. Cancers (Basel) 2020; 12:E2150. [PMID: 32756436 PMCID: PMC7466102 DOI: 10.3390/cancers12082150] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/28/2020] [Accepted: 08/01/2020] [Indexed: 12/17/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with an overall 5-year survival of only 47%. As the development of novel targeted therapies is drastically necessary in order to improve patient survival, current EOC clinical trials have heavily focused on immunotherapeutic approaches, centered upon programmed cell death 1 (PD-1) inhibitors. While PD-1 monotherapies have only exhibited modest responses for patients, it has been theorized that in order to enhance EOC patient response to immunotherapy, combinatorial regimens must be investigated. In this review, unique challenges to EOC PD-1 response will be discussed, along with a comprehensive description of both preclinical and clinical studies evaluating PD-1-based combinatorial therapies. Promising aspects of PD-1-based combinatorial approaches are highlighted, while also discussing specific preclinical and clinical areas of research that need to be addressed, in order to optimize EOC patient immunotherapy response.
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Affiliation(s)
- Nicole E. James
- Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI 02905, USA; (N.E.J.); (M.W.); (P.A.D.)
| | - Morgan Woodman
- Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI 02905, USA; (N.E.J.); (M.W.); (P.A.D.)
| | - Paul A. DiSilvestro
- Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI 02905, USA; (N.E.J.); (M.W.); (P.A.D.)
- Department of Obstetrics and Gynecology, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA
| | - Jennifer R. Ribeiro
- Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI 02905, USA; (N.E.J.); (M.W.); (P.A.D.)
- Department of Obstetrics and Gynecology, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA
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22
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Jikuya R, Kishida T, Sakaguchi M, Yokose T, Yasui M, Hashizume A, Tatenuma T, Mizuno N, Muraoka K, Umemoto S, Kawai M, Yoshihara M, Nakamura Y, Miyagi Y, Sasada T. Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma. Cancer Immunol Immunother 2020; 69:2041-2051. [PMID: 32424467 DOI: 10.1007/s00262-020-02608-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/13/2020] [Indexed: 12/24/2022]
Abstract
Recently, the effectiveness of anti-programmed death 1 (PD-1) antibody therapy in the treatment of renal cell carcinoma (RCC) has been established. Nevertheless, efficacy has been reported to be limited to only 10-30% of patients. To develop more effective immunotherapy for RCC, we analyzed the immunological characteristics in RCC tissues by immunohistochemistry (IHC). We prepared a tissue microarray that consisted of tumor tissue sections (1 mm in diameter) from 83 RCC patients in Kanagawa Cancer Center between 2006 and 2015. IHC analysis was performed with antibodies specific to immune-related (CD8 and Foxp3) and immune checkpoint (programmed death ligand 1 (PD-L1) and 2 (PD-L2), B7-H4 and galectin-9) molecules. The numbers and proportions of positively stained tumor cells or immune cells were determined in each section. From multivariate analysis of all 83 patients, higher galectin-9 expression was detected as a factor associated with worse overall survival (OS) (P = 0.029) and that higher stage and higher B7-H4 expression were associated with worse progression-free survival (PFS) (P < 0.001 and P = 0.021, respectively). Similarly, in multivariate analysis of 69 patients with clear cell RCC, though not statistically significant, there was a trend for association between higher galectin-9 expression and worse OS (P = 0.067), while higher stage was associated with worse PFS (P < 0.001). This study suggests that higher galectin-9 expression is an independent adverse prognostic factor of OS in RCC patients. Therefore, to develop more effective personalized immunotherapy to treat RCC, it may be important to target not only PD-1/PD-L1, but also other immune checkpoint molecules such as galectin-9.
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Affiliation(s)
- Ryosuke Jikuya
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Takeshi Kishida
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.
| | - Masahiko Sakaguchi
- Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Tomoyuki Yokose
- Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Masato Yasui
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Akihito Hashizume
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Tomoyuki Tatenuma
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Nobuhiko Mizuno
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Kentaro Muraoka
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Susumu Umemoto
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Masaki Kawai
- Department of Urology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Mitsuyo Yoshihara
- Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Yoshiyasu Nakamura
- Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Yohei Miyagi
- Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Tetsuro Sasada
- Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan. .,Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.
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Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol 2020; 20:680-693. [PMID: 32269380 DOI: 10.1038/s41577-020-0296-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Abstract
Regulatory T (Treg) cells constitute a dynamic population that is essential for controlling immune responses in health and disease. Defects in Treg cell function and decreases in Treg cell numbers have been observed in patients with autoimmunity and the opposite effects on Treg cells occur in cancer settings. Current research on new therapies for these diseases is focused on modulating Treg cell function to increase or decrease suppressive activity in autoimmunity and cancer, respectively. In this regard, several co-inhibitory receptors that are preferentially expressed by Treg cells under homeostatic conditions have recently been shown to control Treg cell function and stability in different disease settings. These receptors could be amenable to therapeutic targeting aimed at modulating Treg cell function and plasticity. This Review summarizes recent data regarding the role of co-inhibitory molecules in the control of Treg cell function and stability, with a focus on their roles and potential therapeutic use in autoimmunity and cancer.
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Hargadon KM. Tumor microenvironmental influences on dendritic cell and T cell function: A focus on clinically relevant immunologic and metabolic checkpoints. Clin Transl Med 2020; 10:374-411. [PMID: 32508018 PMCID: PMC7240858 DOI: 10.1002/ctm2.37] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/23/2020] [Accepted: 04/23/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer immunotherapy is fast becoming one of the most promising means of treating malignant disease. Cancer vaccines, adoptive cell transfer therapies, and immune checkpoint blockade have all shown varying levels of success in the clinical management of several cancer types in recent years. However, despite the clinical benefits often achieved by these regimens, an ongoing problem for many patients is the inherent or acquired resistance of their cancer to immunotherapy. It is now appreciated that dendritic cells and T lymphocytes both play key roles in antitumor immune responses and that the tumor microenvironment presents a number of barriers to the function of these cells that can ultimately limit the success of immunotherapy. In particular, the engagement of several immunologic and metabolic checkpoints within the hostile tumor microenvironment can severely compromise the antitumor functions of these important immune populations. This review highlights work from both preclinical and clinical studies that has shaped our understanding of the tumor microenvironment and its influence on dendritic cell and T cell function. It focuses on clinically relevant targeted and immunotherapeutic strategies that have emerged from these studies in an effort to prevent or overcome immune subversion within the tumor microenvironment. Emphasis is also placed on the potential of next-generation combinatorial regimens that target metabolic and immunologic impediments to dendritic cell and T lymphocyte function as strategies to improve antitumor immune reactivity and the clinical outcome of cancer immunotherapy going forward.
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Affiliation(s)
- Kristian M. Hargadon
- Hargadon LaboratoryDepartment of BiologyHampden‐Sydney CollegeHampden‐SydneyVirginiaUSA
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25
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Liao P, Wang H, Tang YL, Tang YJ, Liang XH. The Common Costimulatory and Coinhibitory Signaling Molecules in Head and Neck Squamous Cell Carcinoma. Front Immunol 2019; 10:2457. [PMID: 31708918 PMCID: PMC6819372 DOI: 10.3389/fimmu.2019.02457] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/01/2019] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are closely linked with immunosuppression, accompanied by complex immune cell functional activities. The abnormal competition between costimulatory and coinhibitory signal molecules plays an important role in the malignant progression of HNSCC. This review will summarize the features of costimulatory molecules (including CD137, OX40 as well as CD40) and coinhibitory molecules (including CTLA-4, PD-1, LAG3, and TIM3), analyze the underlying mechanism behind these molecules' regulation of the progression of HNSCC, and introduce the clinic application. Vaccines, such as those targeting STING while working synergistically with monoclonal antibodies, are also discussed. A deep understanding of the tumor immune landscape will help find new and improved tumor immunotherapy for HNSCC.
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Affiliation(s)
- Peng Liao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Haofan Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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26
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Balancing cancer immunotherapy and immune-related adverse events: The emerging role of regulatory T cells. J Autoimmun 2019; 104:102310. [PMID: 31421963 DOI: 10.1016/j.jaut.2019.102310] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
Advances in our understanding οf tumor immunity have prompted a paradigm shift in oncology, with the emergence of immunotherapy, where therapeutic agents are used to target immune cells rather than cancer cells. A real breakthrough in the field of immunotherapy came with the use of immune checkpoint inhibitors (ICI), namely antagonistic antibodies that block key immune regulatory molecules (checkpoint molecules), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1, that under physiologic conditions suppress T cell effector function. However, despite the enormous success, a significant proportion of patients do not respond, while responses are frequently accompanied by life-threatening autoimmune related adverse events (irAEs). A major impediment in the effectiveness of ICI immunotherapy is the tumoral resistance, which is dependent on the immunosuppressive nature of tumor microenvironment (TME). Regulatory T cells (Tregs) are among the most abundant suppressive cells in the TME and their presence has been correlated with tumor progression, invasiveness as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express most of the checkpoint molecules such as CTLA4, PD1 and LAG3 and therefore represent a direct target of ICI immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis and avoidance of autoimmunity it is plausible that targeting of Tregs by ICI immunotherapy results in the development of irAEs. Since the use of ICI becomes common, and new immune checkpoint molecules are currently under clinical trials for the treatment of cancer, the occurrence of irAEs is expected to dramatically rise. Herein we review the current literature focusing on the role of Tregs in cancer evolution, ICI response and development of irAEs. Unraveling the complex mechanisms that hinder the tumor immune surveillance and in particular how ICI immunotherapy imprint on Treg activities to promote cancer regression while avoid development of irAEs, will empower the design of novel immunotherapeutic modalities in cancer with increased efficacy and diminished adverse events.
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Expression of costimulatory and inhibitory receptors in FoxP3 + regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches. Adv Cancer Res 2019; 144:193-261. [PMID: 31349899 DOI: 10.1016/bs.acr.2019.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.
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Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis. Semin Cancer Biol 2019; 64:29-35. [PMID: 30716481 DOI: 10.1016/j.semcancer.2019.01.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 01/24/2019] [Accepted: 01/31/2019] [Indexed: 01/05/2023]
Abstract
Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inhibitory receptors such as anti-CTLA4 (ipilimumab and tremelimumab) and anti-PD1 (pembrolizumab and nivolumab)/anti-PD-L1 (atezolizumab) have achieved unprecedented success in cancer treatment by facilitating an effective anti-tumor immune response, at least in part, by blocking Treg mediated immunosuppression. While ICBs have shown remarkable success in cancer immunotherapy, immune-related adverse events (IRAEs) arising from ICB have forced consideration of ways to maintain immune homeostasis post ICB treatment. Preclinical models of IRAEs have shown a negative correlation between Treg numbers and IRAEs. Therefore, understanding the "ying-yang" role of Tregs in the regulation of autoimmunity and anti-tumor immunity is critical to provoking an effective anti-tumor response while maintaining immune homeostasis. Studies aimed at developing effective approaches to minimize IRAEs without compromising anti-tumor immunity are underway. Herein, we discuss 1) the critical role of key co-inhibitory receptors on Treg homeostasis and tumor tolerance; 2) how co-receptor blockade by cancer immunotherapy can lead to autoimmune adverse events; and 3) recently emerging management strategies to minimize autoimmune adverse events arising from ICB.
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Kumar P, Bhattacharya P, Prabhakar BS. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018; 95:77-99. [PMID: 30174217 PMCID: PMC6289740 DOI: 10.1016/j.jaut.2018.08.007] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/22/2018] [Accepted: 08/26/2018] [Indexed: 12/22/2022]
Abstract
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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Affiliation(s)
- Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA.
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Yu J, Zhang H, Sun S, Sun S, Li L. The effects of Tim-3 activation on T-cells in gastric cancer progression. Oncol Lett 2018; 17:1461-1466. [PMID: 30675200 PMCID: PMC6341528 DOI: 10.3892/ol.2018.9743] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 08/17/2018] [Indexed: 12/17/2022] Open
Abstract
The incidence of gastric cancer is high, especially in China. The present study aims to provide a novel therapeutic target for gastric cancer. Peripheral blood, cancerous and paracancerous tissues were collected from patients with gastric cancer. T-cell immunoglobulin mucin domain-3 (Tim-3) expression in T-cells was measured and the correlation between Tim-3 expression and the T staging of gastric cancer was analyzed. The levels of T-cell secreted interferon (IFN)-γ and tumor necrosis factor (TNF)-α were assessed following Tim-3 signaling pathway activation. A nude mouse model of gastric cancer was established and Tim-3-stimulated T-cells were injected into the mice to evaluate tumor growth. The results of the present study demonstrated that Tim-3 expression levels from the paracancerous and cancerous gastric tissues were significantly increased compared with the peripheral blood, while its expression was significantly increased in cancerous compared with paracancerous gastric tissues. With the T staging of gastric cancer increasing, the expression of Tim-3 gradually increased. The activation of the Tim-3 signaling pathway in T-cells may inhibit IFN-γ and TNF-α secretion, and the results from the nude mice tumor model demonstrated that the inhibitory effect on tumor growth by T-cells was reduced by Tim-3 signaling pathway activation. The expression level of Tim-3 on the surface of tumor infiltrating T-cells in gastric cancer tissue increases significantly and the increased Tim-3 signaling may inhibit the function of T-cells. The results suggest that the increased expression of Tim-3 on T-cells may be involved the development of gastric cancer.
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Affiliation(s)
- Jiangtao Yu
- Department of Gastrointestinal Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.,Department of Gastrointestinal Surgery, Weihai Municipal Hospital, Weihai, Shandong 264200, P.R. China
| | - Huanhu Zhang
- Department of Gastrointestinal Surgery, Weihai Municipal Hospital, Weihai, Shandong 264200, P.R. China
| | - Shengbo Sun
- Department of Gastrointestinal Surgery, Weihai Municipal Hospital, Weihai, Shandong 264200, P.R. China
| | - Shaowei Sun
- Department of Gastrointestinal Surgery, Weihai Municipal Hospital, Weihai, Shandong 264200, P.R. China
| | - Leping Li
- Department of Gastrointestinal Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Liu Z, McMichael EL, Shayan G, Li J, Chen K, Srivastava R, Kane LP, Lu B, Ferris RL. Novel Effector Phenotype of Tim-3 + Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients. Clin Cancer Res 2018; 24:4529-4538. [PMID: 29712685 PMCID: PMC6139056 DOI: 10.1158/1078-0432.ccr-17-1350] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 11/06/2017] [Accepted: 04/24/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA-4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Clin Cancer Res; 24(18); 4529-38. ©2018 AACR.
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Affiliation(s)
- Zhuqing Liu
- Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | | | | | - Jing Li
- School of Medicine, Tsinghua University, Beijing, China
| | - Kevin Chen
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Lawrence P Kane
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Binfeng Lu
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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Liu JF, Wu L, Yang LL, Deng WW, Mao L, Wu H, Zhang WF, Sun ZJ. Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:44. [PMID: 29506555 PMCID: PMC5838931 DOI: 10.1186/s13046-018-0713-7] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 02/19/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND T-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in head and neck squamous cell carcinoma (HNSCC) was still not quite clear. METHODS We carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin-9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN-γ. RESULTS We demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. However, the population of CD206+ macrophages was not significantly declined. The increased IFN-γ production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors. CONCLUSIONS The present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC.
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Affiliation(s)
- Jian-Feng Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lei Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lei-Lei Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei-Wei Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Liang Mao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hao Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wen-Feng Zhang
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China. .,Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget 2018; 8:2171-2186. [PMID: 27974689 PMCID: PMC5356790 DOI: 10.18632/oncotarget.13895] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 11/21/2016] [Indexed: 12/31/2022] Open
Abstract
Checkpoint programmed death-1 (PD-1)/programmed cell death ligands (PD-Ls) have been identified as negative immunoregulatory molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-Ls inhibits the function of T cells and tumor-infiltrating lymphocytes (TIL) while increasing the function of immunosuppressive regulatory T cells (Tregs). This condition causes the tumor cells to evade immune response. Thus, the blockade of PD-1/PD-L1 enhances anti-tumor immunity by reducing the number and/or the suppressive activity of Tregs and by restoring the activity of effector T cells. Furthermore, some monoclonal antibodies blockading PD-1/PD-Ls axis have achieved good effect and received Food and Drug Administration approval. The role of PD-1/PD-Ls in tumors has been well studied, but little is known on the mechanism by which PD-1 blocks T-cell activation. In this study, we provide a brief overview on the discovery and regulatory mechanism of PD-1 and PD-L1 dysregulation in tumors, as well as the function and signaling pathway of PD-1 and its ligands; their roles in tumor evasion and clinical treatment were also studied.
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Phenotypic and Functional Properties of Tumor-Infiltrating Regulatory T Cells. Mediators Inflamm 2017; 2017:5458178. [PMID: 29463952 PMCID: PMC5804416 DOI: 10.1155/2017/5458178] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 12/30/2022] Open
Abstract
Regulatory T (Treg) cells maintain immune homeostasis by suppressing excessive immune responses. Treg cells induce tolerance against self- and foreign antigens, thus preventing autoimmunity, allergy, graft rejection, and fetus rejection during pregnancy. However, Treg cells also infiltrate into tumors and inhibit antitumor immune responses, thus inhibiting anticancer therapy. Depleting whole Treg cell populations in the body to enhance anticancer treatments will produce deleterious autoimmune diseases. Therefore, understanding the precise nature of tumor-infiltrating Treg cells is essential for effectively targeting Treg cells in tumors. This review summarizes recent results relating to Treg cells in the tumor microenvironment, with particular emphasis on their accumulation, phenotypic, and functional properties, and targeting to enhance the efficacy of anticancer treatment.
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36
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Idorn M, Olsen M, Halldórsdóttir HR, Skadborg SK, Pedersen M, Høgdall C, Høgdall E, Met Ö, Thor Straten P. Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction. Oncoimmunology 2017; 7:e1412029. [PMID: 29632724 PMCID: PMC5889291 DOI: 10.1080/2162402x.2017.1412029] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 11/21/2017] [Accepted: 11/22/2017] [Indexed: 12/20/2022] Open
Abstract
Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3+ regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4+, CCR5+, CXCR3+ and CXCR4+ T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment.
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Affiliation(s)
- Manja Idorn
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Maria Olsen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Hólmfrídur Rósa Halldórsdóttir
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Signe Koggersbøl Skadborg
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Magnus Pedersen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark.,Department of Oncology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Claus Høgdall
- Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Blegdamsvej 9, København Ø, Denmark
| | - Estrid Høgdall
- Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
| | - Özcan Met
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark.,Department of Oncology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Nørre Allé 41, København N, Denmark
| | - Per Thor Straten
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark.,Department of Pathology, Molecular unit, Danish CancerBiobank, Herlev University Hospital, Herlev ringvej 75, Herlev, Denmark
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Khairallah AS, Genestie C, Auguste A, Leary A. Impact of neoadjuvant chemotherapy on the immune microenvironment in advanced epithelial ovarian cancer: Prognostic and therapeutic implications. Int J Cancer 2017; 143:8-15. [DOI: 10.1002/ijc.31200] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 11/16/2017] [Accepted: 11/22/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Aya S. Khairallah
- Department of Pathology and Laboratory Medicine; Gustave Roussy Cancer Center; Villejuif France
| | - Catherine Genestie
- Department of Pathology and Laboratory Medicine; Gustave Roussy Cancer Center; Villejuif France
| | - Aurélie Auguste
- INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center; Villejuif France
| | - Alexandra Leary
- Department of Pathology and Laboratory Medicine; Gustave Roussy Cancer Center; Villejuif France
- Department of Medical Oncology; Gustave Roussy Cancer Center; Villejuif France
- Faculty of Sciences; University Paris-Sud; Orsay France
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38
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Massa C, Seliger B. The tumor microenvironment: Thousand obstacles for effector T cells. Cell Immunol 2017; 343:103730. [PMID: 29249298 DOI: 10.1016/j.cellimm.2017.12.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 12/04/2017] [Accepted: 12/07/2017] [Indexed: 12/24/2022]
Abstract
The immune system is endowed with the capability to recognize and destroy transformed cells, but even in the presence of an immune infiltrate many tumors do progress. In the last decades new discoveries have shed light into (some of) the underlying mechanisms. Immune effector cells are not only under the influence of immune suppressive cell subsets, but also intrinsically regulated by immune check point molecules that under physiological condition avoid attach of healthy tissue. Moreover, tumor cells are modifying the surrounding microenvironment through secretion of immune modulators as well as via their own metabolism, thus further impairing the development of immune effector functions. Different approaches are currently being evaluated in the clinic to overcome those regulatory mechanisms and to unleash effector T cells.
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Affiliation(s)
- Chiara Massa
- Institute for Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Barbara Seliger
- Institute for Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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39
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Cari L, Nocentini G, Migliorati G, Riccardi C. Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis. Oncoimmunology 2017; 7:e1387705. [PMID: 29308313 DOI: 10.1080/2162402x.2017.1387705] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 09/28/2017] [Accepted: 09/29/2017] [Indexed: 12/27/2022] Open
Abstract
One of the mechanisms of tumor rejection in immune-modulatory treatments is antibody-dependent cell-mediated cytotoxicity (ADCC) of regulatory T cells (Tregs) that infiltrate tumors in which cells expressing activating Fcγ receptors (FcγRs) are present. Our objective was to identify, through a bioinformatics analysis, Treg marker(s) expressed at the highest levels in nine types of human cancers, in order to determine the best targets for ADCC-inducing antitumor antibodies. We analyzed the mRNA levels of 24 surface Treg markers evaluated by the Affymetrix Human Genome U133 Plus 2.0 Array in 5728 cancer samples obtained via the Genevestigator v3 suite. Our analysis was based on overexpression of markers in tumors as compared to healthy tissues (HTs) and correlation between overexpression of the markers and the tumor suppressive microenvironment. Moreover, we evaluated tumoral infiltration of activating FcγR-expressing cells and calculated the ADCC index for each overexpressed marker, as an indicator of whether the marker was a good target for ADCC induction in tumor-infiltrating Tregs. The results demonstrated that the ADCC strategy is unlikely to succeed in colorectal, liver, prostate and ovarian cancers. Moreover, we identified nine Treg markers that could be targeted in the other tumors: 4-1BB, CD39, galectin-9, GITR, IL-21R, LAP, neuropilin-1, TIGIT and TNFR2. GITR and TIGIT were the only markers that could be potentially useful as targets for the treatment of three cancers: non-squamous and squamous NSCLC and breast infiltrating ductal carcinoma. LAP, neuropilin-1 and CD39 presented as good targets in the treatment of renal cell carcinoma. Our findings may have value for the development of new anti-tumor antibodies.
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Affiliation(s)
- Luigi Cari
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Giuseppe Nocentini
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Graziella Migliorati
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Carlo Riccardi
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
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40
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Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells. Oncotarget 2017; 8:82740-82753. [PMID: 29137299 PMCID: PMC5669925 DOI: 10.18632/oncotarget.21098] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/29/2017] [Indexed: 02/04/2023] Open
Abstract
B7x (B7-H4 or B7S1) is a coinhibitory member of the B7 immune checkpoint ligand family that regulates immune function following ligation with its unknown cognate receptors. B7x has limited expression on normal tissues, but is up-regulated on solid human tumors to inhibit anti-tumor immunity and associates with poor clinical prognosis. We assessed the contribution of cytokine stimuli to induce surface B7x expression on cancer cells and the role of tumor-expressed B7x in a murine pulmonary metastasis model, and finally evaluated the potential interaction between B7x and Neuropilin-1, a suggested potential cognate receptor. We showed that pro-inflammatory and anti-inflammatory cytokines IFNγ, TNFα, and IL-10 did not induce expression of B7x on human or murine cancer cells. Following i.v. injection of CT26, a murine colon cancer cell line in the BALB/c background, we observed a significant increase in tumor burden in the lung of B7x-expressing CT26 mice compared to B7x-negative parental CT26 control mice. This was marked by a significant increase in M2 tumor associated macrophages and antigen-specific CD8 T cell exhaustion. Finally, we found through multiple systems that there was no evidence for B7x and Neuropilin-1 direct interaction. Thus, the B7x pathway has an essential role in modulating the innate and adaptive immune cell infiltrate in the tumor microenvironment with its currently unknown cognate receptor(s).
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Akimova T, Zhang T, Negorev D, Singhal S, Stadanlick J, Rao A, Annunziata M, Levine MH, Beier UH, Diamond JM, Christie JD, Albelda SM, Eruslanov EB, Hancock WW. Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. JCI Insight 2017; 2:94075. [PMID: 28814673 DOI: 10.1172/jci.insight.94075] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022] Open
Abstract
Experimental data indicate that FOXP3+ Tregs can markedly curtail host antitumor immune responses, but the properties of human intratumoral Tregs are still largely unknown, in part due to significant methodologic problems. We studied the phenotypic, functional, epigenetic, and transcriptional features of Tregs in 92 patients with non-small-cell lung cancer, comparing the features of Tregs within tumors versus corresponding blood, lung, and lymph node samples. Intratumoral Treg numbers and suppressive function were significantly increased compared with all other sites but did not display a distinctive phenotype by flow cytometry. However, by undertaking simultaneous evaluation of mRNA and protein expression at the single-cell level, we demonstrated that tumor Tregs have a phenotype characterized by upregulated expression of FOXP3 mRNA and protein as well as significantly increased expression of EOS, IRF4, SATB1, and GATA1 transcription factor mRNAs. Expression of these "Treg-locking" transcription factors was positively correlated with levels of FOXP3 mRNA, with highest correlations for EOS and SATB1. EOS had an additional, FOXP3 mRNA-independent, positive correlation with FOXP3 protein in tumor Tregs. Our study identifies distinctive features of intratumoral Tregs and suggests that targeting Treg-locking transcription factors, especially EOS, may be of clinical importance for antitumor Treg-based therapy.
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Affiliation(s)
- Tatiana Akimova
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tianyi Zhang
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dmitri Negorev
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sunil Singhal
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jason Stadanlick
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Abhishek Rao
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael Annunziata
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Matthew H Levine
- Department of Surgery, Penn Transplant Institute, Hospital of the University of Pennsylvania and University of Pennsylvania, Philadelphia, Pennsylvania, USA. Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Ulf H Beier
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joshua M Diamond
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and
| | - Jason D Christie
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and.,Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Steven M Albelda
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and
| | - Evgeniy B Eruslanov
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Wayne W Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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42
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Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 2017; 276:97-111. [PMID: 28258697 DOI: 10.1111/imr.12520] [Citation(s) in RCA: 627] [Impact Index Per Article: 78.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 11/19/2016] [Indexed: 12/13/2022]
Abstract
Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-g-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.
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Affiliation(s)
- Madhumita Das
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.,Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Chen Zhu
- Discovery Biology, Research and Development, Sanofi US, Cambridge, MA, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.,Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.,The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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43
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Yildirim N, Akman L, Acar K, Demir S, Ozkan S, Alan N, Zekioglu O, Terek MC, Ozdemir N, Ozsaran A. Do tumor-infiltrating lymphocytes really indicate favorable prognosis in epithelial ovarian cancer? Eur J Obstet Gynecol Reprod Biol 2017; 215:55-61. [PMID: 28601728 DOI: 10.1016/j.ejogrb.2017.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 06/01/2017] [Accepted: 06/02/2017] [Indexed: 12/24/2022]
Abstract
OBJECTIVE The aim of this study is to evaluate the impact of lymphocyte infiltration on prognostic parameters, recurrence and survival in ovarian cancer. STUDY DESIGN Sixty-two patients who were primarily operated for epithelial ovarian carcinoma between 1997 and 2008 were included. CD3, CD4, CD8, CD20 and FoxP3 expressions were evaluated immunohistochemically on sections obtained from paraffin-embedded tissues. RESULTS Median follow up was 87 months. In whole cohort, CD3+ and CD8+ T lymphocyte infiltrations were significantly higher in patients with high-grade tumors, advanced stage tumors and the patients with omental metastasis (for CD3 p=0.0001, p=0.029, p=0.016; for CD8 p=0.044, p=0.002, p=0.046, respectively). DFS was significantly lower among patients with CD8+ T lymphocytes with regard to patients who did not have CD8+ T lymphocyte infiltration (p=0.028). In univariate analysis, presence of CD8 cytotoxic T lymphocyte infiltration (p=0.03), stage (0.0001), tumor grade (p=0.007), omental metastasis (p=0.0001) and lymph node metastasis (p=0.0001) were significant risk factors for recurrence. But in multivariate analysis, only stage [HR: 116.6 (95% CI: 13.09-1039.45) (p=0.0001)] was found as an independent risk factor for recurrence. CONCLUSION CD3+ and CD8+ T lymphocyte infiltrations were related with advanced stage, high-grade tumor and the omental metastasis in ovarian cancer. DFS was significantly shorter in patients with CD8+ T lymphocyte infiltration. CD3+ and CD8+ T lymphocyte infiltrations were related with poor prognosis in ovarian cancer.
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Affiliation(s)
- Nuri Yildirim
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.
| | - Levent Akman
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
| | - Kamuran Acar
- Ege University, Faculty of Medicine, Department of Pathology, Izmir, Turkey
| | - Sibel Demir
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
| | - Sultan Ozkan
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
| | - Nuran Alan
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
| | - Osman Zekioglu
- Ege University, Faculty of Medicine, Department of Pathology, Izmir, Turkey
| | - M Cosan Terek
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
| | - Necmettin Ozdemir
- Ege University, Faculty of Medicine, Department of Pathology, Izmir, Turkey
| | - Aydin Ozsaran
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey
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44
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Xu Y, Zhang H, Huang Y, Rui X, Zheng F. Role of TIM-3 in ovarian cancer. Clin Transl Oncol 2017; 19:1079-1083. [PMID: 28357631 DOI: 10.1007/s12094-017-1656-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/25/2017] [Indexed: 12/13/2022]
Abstract
Evidences have suggested that immunotherapy for ovarian cancer is effective. Immune checkpoints have emerged in the field of cancer immunotherapy. Multiple studies have shown negative regulation of TIM-3 expression on CD4+ and CD8+ T cells and other immunocytes. Overexpression of TIM-3 in innate immune cells has been found in certain types of tumor. The blockade of TIM-3 leads to sustained anti-tumor reactions. TIM-3 plays an inhibitive role for immunity in ovarian cancer. TIM-3 is involved in the development of various subtypes of ovarian cancer and thus has the potential to be a therapeutic target for treatment of ovarian cancer.
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Affiliation(s)
- Y Xu
- Department of Gynecology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, China.
| | - H Zhang
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL, USA
| | - Y Huang
- Department of Gynecology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, China
| | - X Rui
- Department of Gynecology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, China
| | - F Zheng
- Department of Gynecology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, China
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45
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Greil R, Hutterer E, Hartmann TN, Pleyer L. Reactivation of dormant anti-tumor immunity - a clinical perspective of therapeutic immune checkpoint modulation. Cell Commun Signal 2017; 15:5. [PMID: 28100240 PMCID: PMC5244547 DOI: 10.1186/s12964-016-0155-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/06/2016] [Indexed: 12/17/2022] Open
Abstract
In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion. This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.
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Affiliation(s)
- Richard Greil
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria. .,Salzburg Cancer Research Institute (SCRI) - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria. .,Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) Study Group, Salzburg, Austria. .,Cancer Cluster Salzburg (CCS), Salzburg, Austria.
| | - Evelyn Hutterer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.,Salzburg Cancer Research Institute (SCRI) - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria.,Cancer Cluster Salzburg (CCS), Salzburg, Austria
| | - Tanja Nicole Hartmann
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.,Salzburg Cancer Research Institute (SCRI) - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria.,Cancer Cluster Salzburg (CCS), Salzburg, Austria
| | - Lisa Pleyer
- Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.,Salzburg Cancer Research Institute (SCRI) - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria.,Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) Study Group, Salzburg, Austria.,Cancer Cluster Salzburg (CCS), Salzburg, Austria
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46
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Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study. Sci Rep 2017; 7:40530. [PMID: 28074937 PMCID: PMC5225421 DOI: 10.1038/srep40530] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 12/07/2016] [Indexed: 12/20/2022] Open
Abstract
This study aimed to investigate the less known activation pattern of T lymphocyte populations and immune checkpoint inhibitors on immunocytes in patients with bipolar II disorder depression (BD) or major depression (MD). A total of 23 patients with BD, 22 patients with MD, and 20 healthy controls (HCs) were recruited. The blood cell count of T lymphocyte subsets and the plasma level of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were selectively investigated. The expression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2, on T lymphocytes and monocytes, was detected. In results, blood proportion of cytotoxic T cells significantly decreased in BD patients than in either MD patients or HCs. The plasma level of IL-6 increased in patients with BD and MD. The expression of TIM-3 on cytotoxic T cells significantly increased, whereas the expression of PD-L2 on monocytes significantly decreased in patients with BD than in HCs. These findings extended our knowledge of the immune dysfunction in patients with affective disorders.
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47
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Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease. J Immunol Res 2017; 2017:1236219. [PMID: 28164135 PMCID: PMC5253169 DOI: 10.1155/2017/1236219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 07/21/2016] [Accepted: 12/12/2016] [Indexed: 12/22/2022] Open
Abstract
CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p < 0.01), Th1 (p < 0.001), Tc17 (p < 0.05), and CD8+IL-10+ cells (p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p < 0.01) and Tc17 (p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.
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Yan X, Wu C, Chen T, Santos MM, Liu CL, Yang C, Zhang L, Ren J, Liao S, Guo H, Sukhova GK, Shi GP. Cathepsin S inhibition changes regulatory T-cell activity in regulating bladder cancer and immune cell proliferation and apoptosis. Mol Immunol 2016; 82:66-74. [PMID: 28033540 DOI: 10.1016/j.molimm.2016.12.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 12/17/2016] [Accepted: 12/19/2016] [Indexed: 12/29/2022]
Abstract
Regulatory T cells (Tregs) are immune suppressive cells, but their roles in tumor growth have been elusive, depending on tumor type or site. Our prior study demonstrated a role of cathepsin S (CatS) in reducing Treg immunosuppressive activity. Therefore, CatS inhibition in Tregs may exacerbate tumor growth. Using mouse bladder carcinoma MB49 cell subcutaneous implant tumor model, we detected no difference in tumor growth, whether mice were given saline- or CatS inhibitor-treated Tregs. However, mice that received inhibitor-treated Tregs had fewer splenic and tumor Tregs, and lower levels of tumor and splenic cell proliferation than mice that received saline-treated Tregs. In vitro, inhibitor-treated Tregs showed lower proliferation and higher apoptosis than saline-treated Tregs when cells were exposed to MB49. In contrast, both types of Tregs showed no difference in proliferation when they were co-cultured with normal splenocytes. Inhibitor-treated Tregs had less apoptosis in splenocytes, but more apoptosis in splenocytes with MB49 conditioned media than saline-treated Tregs. In turn, we detected less proliferation and more apoptosis of MB94 cells after co-culture with inhibitor-treated Tregs, compared with saline-treated Tregs. B220+ B-cell, CD4+ T-cell, and CD8+ T-cell proliferation and apoptosis were also lower in splenocytes co-cultured with inhibitor-treated Tregs than with saline-treated Tregs. Under the same conditions, the addition of cancer cell-conditioned media greatly increased CD8+ T-cell proliferation and reduced CD8+ T-cell apoptosis. These observations suggest that CatS inhibition of Tregs may reduce overall T-cell immunity under normal conditions, but enhance CD8+ T-cell immunity in the presence of cancer cells.
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Affiliation(s)
- Xiang Yan
- Department of Urology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Chun Wu
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, 430022, China
| | - Tao Chen
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Marcela M Santos
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Cong-Lin Liu
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Chongzhe Yang
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Lijun Zhang
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jingyuan Ren
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Sha Liao
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Hongqiang Guo
- Department of Urology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China
| | - Galina K Sukhova
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Guo-Ping Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Choi HS, Ha SY, Kim HM, Ahn SM, Kang MS, Kim KM, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kang ES. The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients. Oncotarget 2016; 7:7940-51. [PMID: 26799288 PMCID: PMC4884965 DOI: 10.18632/oncotarget.6958] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 12/26/2015] [Indexed: 12/23/2022] Open
Abstract
The prognostic effects of tumor infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs) and myeloid derived suppressing cells (MDSCs) are inconclusive in gastric cancers. We investigated the frequencies of TILs including CD8+ T cells, CD45+CD4+CD25± FOXP3+ Tregs, CD45+CD11b+ CD14+ HLA−DR− MDSCs in 28 gastric cancer tissues by using multicolor flow cytometry. In gastric cancer tissue, the percentage of Tregs among the CD4+ T cell subset was substantially increased compared to that of Tregs among peripheral blood CD4+ T cells from the controls. High frequency of CD8+ T cells among CD3+ T cells correlated with increased overall survival (OS) (p = 0.005). High frequency of Tregs among CD4+ T cells correlated with increased OS (p < 0.001), and disease-free survival (DFS) (p = 0.039) and was an independent prognostic factor in OS (Hazard ratio: 0.047; 95% confidence interval, 0.006-0.372; p = 0.004). High frequency of MDSCs among total examined cells correlated with decreased OS (p = 0.027) and was an independent prognostic factor in OS (Hazard ratio 8.601; 95% confidence interval, 1.240-59.678; p = 0.029). We have demonstrated that high levels of Tregs among tumor-infiltrating CD4+ T cells were favorable, but an increased proportion of MDSCs was an adverse independent prognostic factor in gastric cancer. Our results may provide important insights for future immunotherapy in gastric cancer.
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Affiliation(s)
- Han Sol Choi
- Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye-Mi Kim
- Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Min Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung-Soo Kang
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Biomedical Research Institute (SBRI), Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun-Suk Kang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines (Basel) 2016; 4:vaccines4030028. [PMID: 27509527 PMCID: PMC5041022 DOI: 10.3390/vaccines4030028] [Citation(s) in RCA: 347] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/27/2016] [Accepted: 08/01/2016] [Indexed: 02/07/2023] Open
Abstract
Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits.
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