Naive T cells in Cancer Immune Evasion and Immunotherapy

T 细胞是大多数癌症类型中抗肿瘤免疫的主要效应成分。的 人类癌症环境中记忆T细胞的表型和功能异质性一直是研究的焦点。 近期研究的热点。我们和其他人已经证明癌症中的代谢改变 微环境可以直接介导记忆和效应T细胞功能障碍。然而，尚不清楚 癌症患者中的初始 T 细胞是否会被癌症代谢所靶向和改变，特别是在 晚期癌症患者。 PD-L1和PD-1阻断和其他类型的检查点治疗靶向、拯救和促进效应T细胞 功能以达到临床反应。然而，尚不清楚幼稚 T 细胞是否以及如何参与 当前的癌症免疫治疗介导的机制。 外周幼稚 T 细胞有平衡的损失和替换。幼稚 T 细胞的分子基础 已经在小鼠的体内平衡中研究了静止。然而，幼稚 T 细胞的性质尚不清楚。 癌症患者以及处于稳态和免疫治疗状态下的荷瘤小鼠模型 设置。初始 T 细胞的改变可能会影响 T 细胞稳态和记忆 T 细胞分化和 荷瘤宿主中的功能。因此，是时候系统地研究幼稚 T 细胞的性质了。 携带肿瘤的宿主。在当前的提案中，我们将研究功能和分子特征以及 卵巢癌患者和几种荷瘤小鼠中初始 T 细胞的治疗相关性 模型。我们的具体目标是： 目标 1 是检验我们的假设，即自噬畸形是肿瘤中幼稚 T 细胞的分子特征。 目标 2 是确定肿瘤中幼稚 T 细胞 FIP200 丢失的分子机制。 目标 3 是检验我们的假设，即初始 T 细胞中的 FIP200 影响自发性和治疗诱导的肿瘤 免疫力。

T cells are the main effector components of anti-tumor immunity in the majority of cancer types. The phenotypic and functional heterogeneity of memory T cells in the human cancer environment have been the focus of recent studies. We and others have shown that the metabolic alteration in the cancer microenvironment can directly mediate memory and effector T cell dysfunction. However, it is unknown whether naïve T cells are targeted and altered by cancer metabolism in patients with cancer, particularly in patients with advanced cancer. PD-L1 and PD-1 blockade and other types of checkpoint therapy target, rescue, and promote effector T cell function to achieve clinical response. However, it is unknown if and how naïve T cells are involved in the current cancer immunotherapy-mediated mechanisms. There is a balanced loss and replacement of naïve T cells in the periphery. The molecular basis of naïve T cell quiescence has been studied in homeostasis in mice. However, the nature of naïve T cells is poorly defined in patients with cancer and in tumor bearing mouse models under homeostatic situation and immunotherapeutic settings. Alteration of naïve T cells may likely affect T cell homeostasis and memory T cell differentiation and functionality in the tumor bearing hosts. Thus, it is time to systemically study the nature of naïve T cells in tumor bearing hosts. In the current proposal, we will investigate the functional and molecular features and therapeutic relevance of naïve T cells in patients with ovarian cancer and in several tumor bearing mouse models. Our specific aims are: Aim 1 is to test our hypothesis that autophagy malformation is a molecular feature of naïve T cells in tumor. Aim 2 is to determine the molecular mechanisms of FIP200 loss in naïve T cells in tumor. Aim 3 is to test our hypothesis that FIP200 in naïve T cells affects spontaneous and therapy-induced tumor immunity.