Reversing melanoma-induced T cell dysfunction

描述（由申请方提供）：有充分的证据表明，黑色素瘤患者可以产生针对其自身肿瘤表达的抗原的免疫应答。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，理解自发性TA特异性T细胞应答促进黑色素瘤消退的失败对于设计旨在克服肿瘤诱导的免疫逃逸的新型治疗干预至关重要。在促成肿瘤对细胞毒性T细胞的抗性的肿瘤诱导的免疫抑制的众多机制中，在动物和人类中的许多实验研究已经表明共抑制途径如程序性死亡1（PD-1）/程序性死亡配体1（PD-L1）相互作用在抑制TA特异性CD 8 + T细胞的效应子功能中的作用。晚期黑色素瘤患者外周血淋巴细胞（PBL）或肿瘤浸润淋巴细胞（TILs）中自发的TA特异性CD 8 + T细胞似乎上调PD-1表达。PD-1是在慢性抗原刺激的背景下TA特异性CD 8 + T细胞扩增的调节剂。然而，在自发TA特异性CD 8 + T细胞上单独的PD-1上调在细胞/细胞基础上与T细胞功能障碍不一致且直接相关。这一关键观察结果提出了一个假设，即包括PD-1在内的多种共抑制受体的共表达可能由高度功能失调/耗竭的T细胞表达，如先前在慢性病毒感染小鼠中的病毒特异性CD 8 + T细胞中观察到的那样。在这里，我们建议解决这个问题，并调查是否其他共抑制分子途径参与TA特异性T细胞功能障碍的晚期黑色素瘤患者。我们还将研究阻断这些通路是否可以与PD-1/PD-L1通路阻断协同作用，以逆转晚期黑色素瘤患者PBL和TIL中TA特异性CD 8+和CD 4 + T细胞的黑色素瘤诱导的T细胞功能障碍。总的来说，从概述的研究中得出的发现将支持在免疫干预中使用组合共抑制途径阻断剂，以逆转晚期黑色素瘤患者中肿瘤诱导的T细胞耗竭/功能障碍。 公共卫生相关性：拟议的研究旨在了解T细胞免疫应答促进黑色素瘤消退的失败。因此，该研究项目对于设计新的治疗干预措施至关重要，这些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有效抗肿瘤反应。

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.