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Targeting TIGIT and PD-1 in Melanoma

靶向黑色素瘤中的 TIGIT 和 PD-1

基本信息

批准号：
10412050
负责人：
HASSANE M ZAROUR
金额：
$ 35.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412050
关键词：
Animals Antibodies Antigen-Presenting Cells Antigens Antitumor Response Applications Grants Binding CD8-Positive T-Lymphocytes CD8B1 gene Cell Death Cell Maturation Cell Survival Cell physiology Cells Chronic Clinical Combination immunotherapy Conflict (Psychology)Cytotoxic T-Lymphocytes Development Dimerization Down-Regulation Engineering Exposure to Failure Frequencies Functional disorder Growth Human ITIM Immune Immune response Immunoglobulins Immunologics Immunosuppression Impairment In Vitro Interleukin-10 Ligands Ligation Melanoma Cell Metalloproteases Metastatic Melanoma MicroRNAs Modeling Monoclonal Antibodies Mus Natural Killer Cells PD-1 blockade PI3K/AKT Pathway interactions Patient-Focused Outcomes Patients Peripheral Blood Lymphocyte Production Regulatory T-Lymphocyte Reporting Resistance Role Signal Transduction Solid Neoplasm T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Time Transforming Growth Factor beta Tumor Antigens Tumor-Infiltrating Lymphocytes anti-PD-1 anti-tumor immune response antigen-specific T cells antitumor effect base cancer immunotherapy clinical effect combinatorial design effector T cell efficacy testing exhaust immunological synapse formation improved in vivo melanoma neoplastic cell novel novel therapeutic intervention novel therapeutics programmed cell death protein 1 receptor tumor tumor immunology tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT There is ample evidence that patients with melanoma can develop immune responses directed against antigens expressed by their tumor. However, high tumor antigen (TA)-specific cytotoxic T cell (CTL) frequencies often fail to induce melanoma rejection. Understanding the failure of TA-specific T cells to promote tumor regression is, therefore, critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape. Among the numerous mechanisms of tumor-induced immunosuppression that contribute to the resistance of tumors to CTLs, a number of studies in animals and humans have suggested the role of inhibitory pathways in impeding CTL effector functions. TA-specific CD8+T cells in peripheral blood lymphocytes (PBLs) or tumor-infiltrating lymphocytes (TILs) of patients with advanced melanoma upregulate the expression of multiple inhibitory receptors (IRs), including PD1, Tim3, and TIGIT. We have previously shown that these IRs interact with their ligands expressed in the tumor microenvironment to impede of TA- specific CD8+ T cell expansion and functions in the context of chronic antigen stimulation. In particular, we have shown for the first time that TIGIT blockade adds to PD-1 blockade to increase TA-specific CD8+T cell functions in vitro. We have also reported that CD8+TILs in metastatic melanoma downregulate the costimulatory receptor CD226, which competes with TIGIT for binding to the same ligands. Interestingly, TIGIT is also upregulated by highly suppressive CD4+ regulatory T cells (Tregs). The mechanisms supporting the role of TIGIT in regulating Tregs and CD8+T cells remains poorly understood. Based on novel findings, we propose to investigate the mechanisms supporting the role of TIGIT and TIGIT/CD226 imbalance in regulating Tregs and CD8+T cells, respectively, in melanoma. We will also investigate the role of CD226 in regulating anti-tumor immune responses and tumor rejection upon dual PD-1/TIGIT blockade in vivo in mouse-bearing melanoma. Finally, we will test the efficacy of novel Fc-engineered anti-mouse TIGIT antibodies to target Tregs or CD8+TILs in vivo, and promote tumor rejection in combination with PD1 blockade. Collectively, the information derived from the outlined studies will serve as a rationale for the development of novel therapeutic strategies to reverse tumor-induced T cell dysfunction in patients with advanced melanoma and increase the likelihood of clinical benefits.

项目总结/文摘