Anti-tumor and autoimmunity signatures in Down syndrome

摘要/摘要 这是对R01 CA231226的包含项目的行政补充的请求，该项目定义 T细胞对肿瘤和自身抗原的反应特征可作为检查点治疗反应的预测因子。这个 行政补编的拟议研究属于主动父母补助金的范围，重点是 唐氏综合症(DS)，并解决包括项目优先考虑的三个组成部分中的两个 (构成部分1：与DS和构成部分2高度相关的有针对性的高风险-高回报基础科学研究 聚集一大群患有DS的人进行深入的表型鉴定和研究 共存的条件。我们的目标是：1)定义一个最佳的抗肿瘤信号通过表征 合并自身免疫性疾病的DS患者的免疫状况，然后与 免疫检查点抑制剂(ICI)治疗后发生IRAE的实体瘤患者的免疫状况 治疗，以确定最佳的抗肿瘤信号(组件1)；和2)扩展我们现有的DS 包括更多成人和更多患有共生自身免疫性疾病的个人的生物存储库(组件 2)。拟议研究的中心假设是DS的免疫功能促进了 自身免疫是保护实体瘤和促进治疗反应的相同免疫特征。 接受ICI治疗。这是基于1)观察结果，即DS患者可以免受实体肿瘤的侵袭 也易患自身免疫；2)越来越多的证据表明治疗与 ICI治疗的反应和自身免疫性irAEs的发展。目标1的目标是增加两个 我们现有的成人数量和患有共生自身免疫性疾病的个人数量 生物储存库。目标2的目标是通过识别共享的 DS患者和ICI患者之间的免疫结构特征 伊莱。这些研究将确定全球免疫格局和抗原特异性T细胞反应 患有DS和共发自身免疫性甲状腺疾病的个体，然后与癌症患者进行比较 发展为ICI诱导的自身免疫性甲状腺炎。全球免疫格局将用MASS来描述 细胞计数和RNA测序。抗原特异性T细胞的频率和表型将用 转录和表位的激活诱导分析和单细胞测序 (scCite-seq)。拟议的工作将扩大对抗肿瘤机制的理解，从而改善ICI 结果并阐明在不降低抗-抗的情况下减轻DS患者自身免疫的可能方法 肿瘤效应。重要的是，这是在家长奖的范围内，因为它侧重于理解T细胞 ICI治疗后发生irAEs的个体的反应。它还利用专业知识和资源 已在母基金中到位，并采用与母基金相同的方法和实验设计 GRANT评估全球免疫格局和抗原特异性T细胞。

Summary/Abstract This is a request for an Administrative Supplement for the INCLUDE Project for R01 CA231226 “Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy”. The proposed studies for the Administrative Supplement are within the scope of the active parent grant, focused on Down syndrome (DS) and address two of the three components prioritized by the INCLUDE Project (Component 1: Targeted high risk – high reward basic science studies highly relevant to DS and Component 2 Assembly of a large cohort of individuals with DS across the lifespan to perform deep phenotyping and study co-existing conditions. Our objectives are: 1) To define an optimal anti-tumor signature by characterizing the immune landscape in individuals with DS with co-occurring autoimmune disease and then comparing to the immune landscape in patients with solid tumors who develop irAE after immune checkpoint inhibitor (ICI) therapy in order to identify an optimal anti-tumor signature (Component 1); and 2) Expand our existing DS biorepository to include more adults and more individuals with co-occurring autoimmune disease (Component 2). The central hypothesis for the proposed studies is that the immune features in DS that promote autoimmunity are the same immune features that protect from solid tumors and promote therapeutic response to ICI therapy. It is based on 1) observations that people with DS are protected from developing solid tumors and also predisposed to autoimmunity; and 2) Growing evidence of an association between therapeutic response to ICI therapy and development of autoimmune irAEs. The goal of Aim 1 is to increase both the number of adults and the number of individuals with co-occurring autoimmune disease in our existing biorepository. The goal of Aim 2 is to define an optimal anti-tumor signature by identifying shared characteristics of the immune architecture between people with DS and those treated with ICI who develop an irAE. These studies will determine the global immune landscape and antigen-specific T cell responses in individuals with DS and co-occurring autoimmune thyroid disease and then compare to cancer patients who develop ICI induced-autoimmune thyroiditis. The global immune landscape will be characterized using mass cytometry and RNA-sequencing. Antigen-specific T cell frequency and phenotype will be determined using activation-induced assays and single cell Cellular Indexing of Transcriptomes and Epitopes by Sequencing (scCITE-seq). The proposed work will extend understanding of anti-tumor mechanisms and thus improve ICI outcomes and elucidate potential ways to mitigate autoimmunity in people with DS without diminishing anti- tumor effect. Importantly, it is within the scope of the parent award as it focuses on understanding T cell responses in individuals that develop irAEs after ICI therapy. It also leverages the expertise and resources already in place in the parent grant and utilizes the same approach and experimental design as the parent grant to assess the global immune landscape and antigen-specific T cells.