Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC

程序性细胞死亡-1(PD-1)靶向治疗改变了肺癌治疗的格局1。 虽然已经产生了一些令人印象深刻的结果，但决定哪些患者愿意或将 不，对这种待遇的反应都没有很好的界定。了解免疫因素是很重要的。 与临床反应相关联，不仅是为了改进当前的治疗，也是为了确定预测性 生物标志物。我们最近发现了一个新的PD-1 TCF-1 CD28 CD8 T细胞群体。 T细胞耗竭小鼠模型中的细胞样特征6-8。PD-1后CD8T细胞的增殖暴发 BLOCK来自这种干细胞样的CD8 T细胞群，并依赖于共刺激信号 CD28分子。重要的是，我们的初步数据表明，干细胞样CD8T细胞存在于非小细胞 细胞肺癌(NSCLC)患者。根据我们的观察，我们假设干细胞样CD8 T细胞 在非小细胞肺癌患者成功的PD-1靶向治疗中发挥关键作用。这次会议的主要目标之一是 建议在非小细胞肺癌患者中鉴定和鉴定这些干细胞样CD8 T细胞。另一点很重要 在这项提案中要解决的问题是，这些干细胞样CD8T细胞的存在是否与增殖相关 CD8T细胞应答及免疫治疗的临床疗效以下是具体目标 为实现我们的目标提出的建议： 目的1：鉴定和鉴定干细胞样CD8T细胞的表型、定位和功能。 肺癌患者。目标1a。描述转录、表观遗传和功能特征 非小细胞肺癌中肿瘤浸润性干细胞样CD8 T细胞；目的1b。确定T细胞之间的克隆关系 用TCR测序法测定肿瘤、引流淋巴结和血液中的种群。 目的：研究PD-1和mTOR联合抑制小鼠卵巢癌的疗效和免疫应答。 非小细胞肺癌患者的新辅助治疗试验。目标2a。观察联合用药的临床疗效 早期非小细胞肺癌患者新辅助治疗试验中PD-1和mTOR的抑制。目标2b。至 检测免疫应答与联合治疗临床疗效之间的相关性。 目的：应用体内氚标记技术评价肺癌患者的T细胞动力学。目标3a。至 用活体氚标记测量非小细胞肺癌患者T细胞群的增殖。目标3b。至 体内测定mTOR和PD1阻断后增殖的CD8T细胞群 氚标记。

Programmed cell death-1 (PD-1) targeted therapies have changed the landscape of lung cancer treatment1. While some impressive results have been generated, the mechanisms that dictate which patients will, or will not, respond to this treatment are not well defined. It is important to understand the immunological factors associated with clinical responses not only to improve current therapies but also to identify predictive biomarkers. We have recently identified a novel population of PD-1+ TCF-1+ CD28+ CD8 T cells with stem- cell-like features in a mouse model of T cell exhaustion6-8. The proliferative burst of CD8 T cells after PD-1 blockade comes from this stem-like CD8 T cell population, and is dependent on signals from costimulatory molecule CD28. Importantly, our preliminary data suggest that stem-like CD8 T cells are present in non-small cell lung cancer (NSCLC) patients. Based on our observations, we hypothesize that the stem- like CD8 T cells play a critical role in successful PD-1 targeted therapies in NSCLC patients. One of the major goals of this proposal is to identify and characterize these stem-like CD8 T cells in NSCLC patients. Another important point to be addressed in this proposal is if the presence of these stem-like CD8 T cells correlates with proliferative responses of CD8 T cells as well as clinical efficacy of the immunotherapies. The following Specific Aims are proposed to achieve our goals: Aim 1: To identify and characterize the phenotype, location, and function of stem-like CD8 T-cells in lung cancer patients. Aim 1a. Characterize the transcriptional, epigenetic, and functional characteristics of tumor infiltrating stem-like CD8 T cells in NSCLC; Aim 1b. Determine the clonal relationship between T-cell populations in tumor, draining lymph node, and blood using TCR sequencing. Aim 2: To study the efficacy and immune responses of combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial in NSCLC patients. Aim 2a. To examine the clinical efficacy of the combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial for patients with early stage NSCLC. Aim 2b. To examine the correlation between immune responses and clinical efficacy of the combination therapy. Aim 3: To evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling. Aim 3a. To measure proliferation in T cell populations in NSCLC patients using in vivo deuterium labeling. Aim 3b. To determine the CD8 T cell populations that proliferate in response to mTOR and PD1 blockade using in vivo deuterium labeling.