Targeting TIGIT and PD-1 in Melanoma

项目摘要/摘要 有充分的证据表明，黑色素瘤患者可以产生针对 他们的肿瘤所表达的抗原。然而，高肿瘤抗原(TA)特异性细胞毒性T细胞(CTL) 频率往往不能诱导黑色素瘤排斥反应。理解TA特异性T细胞未能促进 因此，肿瘤消退对于设计新的旨在克服 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， 在动物和人类身上的一些研究表明，肿瘤对CTL的耐药性是有贡献的 抑制通路在阻碍CTL效应功能中的作用。外周血中Ta特异的CD8 T细胞 晚期黑色素瘤患者外周血淋巴细胞或肿瘤浸润性淋巴细胞上调 多种抑制受体的表达，包括PD1、TIM3和TIGIT。我们之前已经 研究表明，这些IR与其在肿瘤微环境中表达的配体相互作用，以阻止TA- 特异性CD8T细胞在慢性抗原刺激下的增殖和功能。特别是，我们 首次表明TIGIT阻滞剂增加了PD-1阻断剂以增加TA特异性CD8 T细胞 在体外发挥作用。我们还报道，转移性黑色素瘤中的CD8 TIL下调 共刺激受体CD226，它与TIGIT竞争结合相同的配体。有趣的是，TIGIT 也被高度抑制的CD4调节性T细胞(Tregs)上调。支持这一角色的机制 TIGIT在调节Tregs和CD8T细胞中的作用尚不清楚。基于新的发现，我们建议 TIGIT和TIGIT/CD226失衡在Tregs调控中的作用机制研究 和CD8T细胞在黑色素瘤中的表达。我们还将研究CD226在调节抗肿瘤方面的作用 荷瘤小鼠体内双重PD-1/TIGIT阻断后的免疫反应和肿瘤排斥反应。 最后，我们将测试针对Tregs或Tregs的新型Fc工程抗鼠TIGIT抗体的有效性 CD8TIL在体内，并联合PD1阻断促进肿瘤排斥反应。总而言之，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础 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 临床益处。

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.