Targeting TIGIT and PD-1 in Melanoma

项目总结/摘要 有充分的证据表明，黑色素瘤患者可以产生针对 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素瘤排斥。理解TA特异性T细胞促进 因此，肿瘤消退对于设计旨在克服癌症的新的治疗干预至关重要。 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，许多动物和人类的研究表明， 抑制途径在阻碍CTL效应子功能中的作用。外周血中TA特异性CD 8 +T细胞 晚期黑色素瘤患者的外周血淋巴细胞（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PD 1、Tim 3和TIGIT。我们先前已经 表明这些IR与肿瘤微环境中表达的配体相互作用，以阻止TA- 特异性CD 8 + T细胞扩增和功能的背景下，慢性抗原刺激。我们尤其 已经首次显示TIGIT阻断增加PD-1阻断以增加TA特异性CD 8 +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CD 8 +TILs下调了肿瘤细胞的增殖。 共刺激受体CD 226，其与TIGIT竞争结合相同的配体。有趣的是，TIGIT 也被高度抑制性CD 4+调节性T细胞（TCFs）上调。支持这一作用的机制 TIGIT在调节T细胞和CD 8 +T细胞中的作用仍然知之甚少。基于新的发现，我们建议 研究支持TIGIT和TIGIT/CD 226失衡在调节T细胞凋亡中的作用的机制。 和CD 8 +T细胞。我们还将研究CD 226在调节抗肿瘤作用中的作用。 在携带黑色素瘤的小鼠体内双重PD-1/TIGIT阻断后的免疫应答和肿瘤排斥。 最后，我们将测试新型Fc工程化的抗小鼠TIGIT抗体靶向TIGIT或TIGIT的功效。 CD 8 + TIL在体内的表达，并与PD 1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， 临床获益。

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.