Targeting TIGIT and PD-1 in Melanoma

靶向黑色素瘤中的 TIGIT 和 PD-1

• 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
• 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

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.

项目摘要/摘要 有充分的证据表明，黑色素瘤患者可以发展针对的免疫反应 抗原由肿瘤表达。但是，高肿瘤抗原（TA）特异性细胞毒性T细胞（CTL） 频率通常无法诱导黑色素瘤排斥。了解TA特异性T细胞促进的失败 因此，肿瘤回归对于旨在克服的新型治疗干预措施的设计至关重要 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 有助于肿瘤对CTL的抗性，对动物和人类的许多研究表明 抑制途径在阻碍CTL效应函数的作用。外周血中的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（TILS）上调 多种抑制受体（IRS）的表达，包括PD1，TIM3和Tigit。我们以前有 表明这些IR与在肿瘤微环境中表达的配体相互作用，以阻碍Ta- 在慢性抗原刺激的背景下，特定的CD8+ T细胞膨胀和功能。特别是我们 首次表明Tigit封锁增加了PD-1封锁以增加TA特异性CD8+T细胞 体外功能。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，它与Tigit竞争与同一配体结合。有趣的是，Tigit 高度抑制的CD4+调节T细胞（Tregs）也将上调。支持角色的机制 调节Treg和CD8+T细胞中的Tigit仍然对其进行了鲜为人知的理解。根据新颖的发现，我们提出 研究支持Tigit和Tigit/CD226在调节Tregs中的作用的机制 和黑色素瘤中的CD8+T细胞分别。我们还将研究CD226在调节抗肿瘤中的作用 双重PD-1/TIGIT封锁在体内含有小鼠黑色素瘤中的免疫反应和肿瘤排斥。 最后，我们将测试新型FC设计的抗小鼠Tigit抗体对靶Treg或 CD8+TIL在体内，并促进肿瘤排斥与PD1阻滞结合。总体而言，信息 从概述的研究中得出的将是发展新型治疗策略的理由 反向肿瘤诱导的晚期黑色素瘤患者的T细胞功能障碍，并增加 临床益处。