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.

项目概要/摘要有充分的证据表明黑色素瘤患者可以产生针对黑色素瘤的免疫反应其肿瘤表达的抗原。然而，高肿瘤抗原（TA）特异性细胞毒性T细胞（CTL）频率通常不能诱导黑色素瘤排斥。了解 TA 特异性 T 细胞未能促进因此，肿瘤消退对于设计旨在克服肿瘤问题的新型治疗干预措施至关重要。肿瘤诱导的免疫逃逸。在肿瘤诱导的免疫抑制的众多机制中，大量动物和人类研究表明，有助于肿瘤对 CTL 的抵抗抑制途径在阻碍 CTL 效应器功能中的作用。外周血中TA特异性CD8+T细胞晚期黑色素瘤患者的淋巴细胞（PBL）或肿瘤浸润淋巴细胞（TIL）上调多种抑制性受体 (IR) 的表达，包括 PD1、Tim3 和 TIGIT。我们之前有过结果表明，这些 IR 与其在肿瘤微环境中表达的配体相互作用，从而阻碍 TA- 慢性抗原刺激背景下特异性 CD8+ T 细胞扩增和功能。特别是，我们首次证明 TIGIT 阻断可与 PD-1 阻断相结合，以增加 TA 特异性 CD8+T 细胞在体外发挥作用。我们还报道了转移性黑色素瘤中的 CD8+TIL 下调共刺激受体 CD226，与 TIGIT 竞争结合相同的配体。有趣的是，蒂吉特高度抑制性 CD4+ 调节性 T 细胞 (Treg) 也会上调。支持角色的机制 TIGIT 在调节 Tregs 和 CD8+T 细胞中的作用仍知之甚少。基于新颖的发现，我们建议研究支持 TIGIT 和 TIGIT/CD226 失衡在调节 Tregs 中的作用的机制和 CD8+T 细胞，分别在黑色素瘤中。我们还将研究CD226在调节抗肿瘤方面的作用小鼠黑色素瘤体内双重 PD-1/TIGIT 阻断后的免疫反应和肿瘤排斥。最后，我们将测试新型 Fc 工程化抗小鼠 TIGIT 抗体针对 Tregs 或 CD8+TILs 在体内，与 PD1 阻断联合促进肿瘤排斥。总的来说，信息从概述的研究中得出的结论将作为开发新的治疗策略的基本原理逆转晚期黑色素瘤患者肿瘤诱导的 T 细胞功能障碍，并增加发生癌症的可能性临床益处。