Reversing melanoma-induced T cell dysfunction

描述(由申请人提供)：有充分的证据表明，黑色素瘤患者可以针对他们自己的肿瘤表达的抗原产生免疫反应。然而，非常高频率的自发或疫苗诱导的肿瘤抗原(TA)特异性细胞毒性T细胞(CTL)未能诱导黑色素瘤排斥反应。因此，了解自发的TA特异性T细胞反应未能促进黑色素瘤的消退，对于设计旨在克服肿瘤诱导的免疫逃逸的新型治疗干预措施至关重要。在肿瘤诱导免疫抑制的众多机制中，许多动物和人类的实验研究表明，共抑制通路如程序性死亡1(PD-1)/程序性死亡配体1(PD-L1)相互作用在抑制TA特异性CD8+T细胞的效应功能中起作用。晚期黑色素瘤患者外周血淋巴细胞(PBL)或肿瘤浸润性淋巴细胞(TIL)中自发的TA特异性CD8+T细胞可上调PD-1的表达。PD-1是在慢性抗原刺激背景下TA特异性CD8+T细胞增殖的调节因子。然而，在每个细胞的基础上，PD-1单独上调自发的TA特异性CD8+T细胞与T细胞功能障碍并不一致和直接相关。这一关键的观察结果提出了一种假设，即包括PD-1在内的多种共抑制受体的共同表达可能是由高度功能障碍/耗竭的T细胞表达的，就像以前在慢性病毒感染小鼠的病毒特异性CD8+T细胞中观察到的那样。在这里，我们建议解决这个问题，并调查其他共抑制分子通路是否与晚期黑色素瘤患者的TA特异性T细胞功能障碍有关。我们还将研究这些通路的阻断是否与PD-1/PD-L1通路的阻断协同作用，逆转黑色素瘤诱导的晚期黑色素瘤患者PBL和TIL中TA特异性CD8+和CD4+T细胞的功能障碍。总而言之，从概述的研究中得出的发现将支持在免疫治疗干预中使用组合共抑制通路阻断，以逆转晚期黑色素瘤患者由肿瘤引起的T细胞耗竭/功能障碍。 公共卫生相关性：这项拟议的研究旨在了解T细胞免疫反应未能促进黑色素瘤的消退。因此，这一研究项目对于设计新的治疗干预措施至关重要，该干预措施旨在克服肿瘤诱导的免疫逃逸，并刺激黑色素瘤患者的强大抗肿瘤反应。

DESCRIPTION (provided by applicant): There is ample evidence that patients with melanoma can develop immune responses directed against antigens expressed by their own tumor. However, very high frequencies of spontaneous or vaccine-induced tumor antigen (TA)-specific cytotoxic T cells (CTLs) have failed to induce melanoma rejection. Understanding the failure of spontaneous TA-specific T cell responses to promote regression of melanoma 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 cytotoxic T cells, a number of experimental studies in animals and in humans have suggested the role of co- inhibitory pathways like programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions in inhibiting the effector functions of TA-specific CD8+ T cells. Spontaneous TA-specific CD8+ T cells in peripheral blood lymphocytes (PBLs) or tumor-infiltrating lymphocytes (TILs) of patients with advanced melanoma appear to upregulate PD-1 expression. PD-1 is a regulator of TA-specific CD8+ T cell expansion in the context of chronic antigen stimulation. However, PD-1 upregulation alone on spontaneous TA-specific CD8+ T cells is not consistently and directly associated with T cell dysfunction on a cell-per-cell basis. This critical observation raises the hypothesis that the co-expression of multiple co-inhibitory receptors including PD-1 may be expressed by highly dysfunctional/exhausted T cells, as previously observed in virus-specific CD8+ T cells in mice with chronic viral infections. Here, we propose to address this question and investigate whether other co-inhibitory molecular pathways are involved in TA-specific T cell dysfunction in patients with advanced melanoma. We will also investigate whether blockade of these pathways may act synergistically with PD-1/PD-L1 pathway blockade to reverse melanoma-induced T cell dysfunction of TA-specific CD8+ and CD4+ T cells in PBLs and TILs of patients with advanced melanoma. Collectively, the findings derived from the outlined studies will support the use of combinatorial co-inhibitory pathway blockades in immunotherapeutic interventions to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma. PUBLIC HEALTH RELEVANCE: The proposed study aims at understanding the failure of T cell immune responses to promote melanoma regression. This research project is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape and stimulating potent anti-tumor responses in melanoma patients.