Naive T cells in Cancer Immune Evasion and Immunotherapy

在大多数癌症类型中，T细胞是抗肿瘤免疫的主要效应成分。这个 人类癌症环境中记忆T细胞的表型和功能异质性一直是 最近研究的焦点。我们和其他人已经证明，癌症中的代谢变化 微环境可直接介导记忆和效应性T细胞功能障碍。然而，它是未知的 单纯T细胞是否被癌症患者的癌症代谢所靶向和改变，尤其是在 晚期癌症患者。 PD-L1和PD-1阻断等类型的检查点治疗靶向、挽救和促进效应性T细胞 功能以实现临床反应。然而，目前尚不清楚幼稚T细胞是否以及如何参与了 目前癌症免疫治疗的介导机制。 在外周有幼稚T细胞的平衡丢失和替换。幼稚T细胞的分子基础 在小鼠的体内平衡方面，已经研究过静止期。然而，幼稚T细胞的性质在 肿瘤患者及荷瘤小鼠模型的动态平衡及免疫治疗 设置。幼稚T细胞的改变可能影响T细胞的稳态和记忆性T细胞的分化 荷瘤宿主的功能。因此，现在是时候系统地研究人类幼稚T细胞的性质了。 荷瘤宿主。在目前的提案中，我们将研究其功能和分子特征，并 原始T细胞在卵巢癌患者和几种荷瘤小鼠中的治疗意义 模特们。我们的具体目标是： 目的1是验证我们的假设，即自噬畸形是肿瘤中幼稚T细胞的一个分子特征。 目的2探讨肿瘤中幼稚T细胞FIP200缺失的分子机制。 目标3是验证我们的假设，即幼稚T细胞中的FIP200影响自发性和治疗诱导的肿瘤 豁免权。

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.