BLIMP-1 mediated regulation of CD8+ TIL

描述（由申请人提供）：T细胞对其靶点的敏感性和特异性为免疫治疗在癌症控制中的应用提供了可观的前景。然而，在许多情况下，肿瘤内发现的T细胞功能失调。这种功能失调状态的主要原因是抑制分子的表达。我们发现小鼠和人类肿瘤浸润CD8+细胞毒性T细胞时抑制分子的表达与转录因子BLIMP-1的表达密切相关。在这个应用中，我们发现与CD8+ T细胞相比，肿瘤浸润的CD8+ T细胞对急性病毒感染的反应过表达BLIMP-1。我们发现限制肿瘤浸润淋巴细胞中BLIMP-1的表达导致抑制分子表达减少和功能活性增加。此外，我们发现BLIMP-1的表达比抑制分子的表达更能控制CD8+ T细胞的功能。根据这些数据，我们建议开展研究，以确定BLIMP-1表达如何在肿瘤浸润淋巴细胞中受到调节，并确定BLIMP-1表达如何调节肿瘤浸润淋巴细胞的功能。本文提出的研究将阐明肿瘤浸润性淋巴细胞功能障碍背后的机制，并将为开发预防功能障碍或恢复功能障碍的干预措施提供机会

DESCRIPTION (provided by applicant): The exquisite sensitivity and specificity of T cells for their targets offers considerable promise for the use of immunotherapy in cancer control. However, in many instances, T cells found within tumors are dysfunctional. A major cause for this dysfunctional state is the expression of inhibitory molecules. We have found that the expression of inhibitory molecules by both murine and human tumor infiltrating CD8+ cytotoxic T cells correlates strongly with the expression of the transcription factor BLIMP-1. In this application we show that tumor infiltrating CD8+ T cells over-express BLIMP-1 compared to CD8+ T cells responding to acute viral infection. We show that limiting BLIMP-1 expression in tumor infiltrating lymphocytes results in reduced inhibitory molecule expression and increased functional activity. Further, we show that BLIMP-1 expression controls CD8+ T cell function beyond the expression of inhibitory molecules. From these data, we propose to pursue studies that will define how BLIMP-1 expression is regulated in tumor infiltrating lymphocytes, and will determine how BLIMP-1 expression regulates tumor infiltrating lymphocyte function. The studies presented here will illuminate the mechanisms behind tumor infiltrating lymphocyte dysfunction, and will provide opportunities to develop interventions that either prevent dysfunction, or restore activity.