Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy

项目总结/摘要 免疫检查点抑制剂疗法已经彻底改变了实体瘤肿瘤学领域-特别是，它们 在提高晚期肺癌或膀胱癌患者的生存率方面发挥了重要作用。 然而，尽管临床上取得了成功，免疫检查点抑制剂并不是在所有情况下都有效， 与严重的免疫相关不良事件有关。此应用程序是为了响应国家癌症 研究所的挑衅性问题#8：“免疫相关不良反应发生的预测生物标志物是什么？ 与检查点抑制相关的irAE事件，它们是否与疗效标志物相关？”的目标 提出的研究是确定T细胞生物标志物，预测与ICI相关的自身免疫相关的irAE 疗法这些研究的中心假设是，T细胞的频率和表型 对自身抗原具有特异性可预测自身免疫性irAE，这反过来又可预测某些患者的治疗效果。 患者以下四个具体目标将解决这一假设。目标1研究将确定免疫 检查点抑制剂治疗改变肿瘤和自身抗原特异性T细胞的频率和表型 使用创新的方法分离抗原特异性T细胞，以及之前和之后的纵向受试者队列， 免疫检查点抑制剂治疗后。目标2研究将使用创新的单细胞RNA测序 一种方法来确定免疫检查点抑制剂治疗是否会产生扩增的T细胞克隆，以及 这些T细胞具有预测抗肿瘤和自身免疫应答的表型或功能特性。目的 3项研究将确定免疫检查点抑制剂治疗是否会改变CD 4和CD 8 T细胞格局 在癌症中，它类似于在具有天然自身免疫性的个体中看到的。Aim 4研究将测试 假设免疫检查点抑制剂疗法将静止的自身反应性T细胞从调节中释放， 导致与整体T细胞应答不同的频率和活化增加。这些研究一起 将系统阐明免疫检查点后肿瘤免疫和自身免疫之间的关系 抑制剂治疗，并将提供洞察T细胞生物标志物的潜力，以预测临床结果。

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitor therapies have revolutionized the field of solid tumor oncology - in particular, they have played a substantial role in improving the survival of patients with advanced lung or bladder cancer. However, despite clinical successes, immune checkpoint inhibitors are not effective in all cases, and may be associated with serious immune-related adverse events. This application is in response to the National Cancer Institute’s Provocative Question #8: “What are the predictive biomarkers for the onset of immune-related adverse events (irAE) associated with checkpoint inhibition, and are they related to markers for efficacy?” The goal of the proposed studies is to identify T cell biomarkers that predict autoimmune-related irAE associated with ICI therapy. The central hypothesis for the proposed studies is that the frequency and phenotype of T cells specific for self-antigens predicts autoimmune irAE, which in turn predicts therapeutic efficacy in some patients. The following four Specific Aims will address this hypothesis. Aim 1 studies will determine how immune checkpoint inhibitor therapy alters the frequency and phenotype(s) of tumor- and autoantigen-specific T cells using an innovative approach to isolate antigen-specific T cells, and a longitudinal cohort of subjects before and after immune checkpoint inhibitor therapy. Aim 2 studies will use an innovative single cell RNA-sequencing approach to determine if expanded T cell clones arise with immune checkpoint inhibitor therapy, and whether these T cells have phenotypic or functional properties predictive of anti-tumor and autoimmune responses. Aim 3 studies will determine whether immune checkpoint inhibitor therapy alters the CD4 and CD8 T cell landscape in cancer making it similar to that seen in individuals with natural autoimmunity. Aim 4 studies will test the hypothesis that immune checkpoint inhibitor therapy releases quiescent autoreactive T cells from regulation, leading to increased frequency and activation distinct from the global T cell response. Together, these studies will systematically elucidate the relationship between tumor- and auto- immunity following immune checkpoint inhibitor therapy, and will provide insight into the potential of T cell biomarkers to predict clinical outcome.