Anti-tumor and autoimmunity signatures in Down syndrome

总结/摘要 这是对R 01 CA 231226“定义 T细胞对肿瘤和自身抗原的应答特征作为对检查点疗法的应答的预测因子”。的 行政补助金的拟议研究属于在职父母补助金的范围，重点是 唐氏综合征（DS），并解决纳入项目优先考虑的三个组成部分中的两个 （组成部分1：与DS和组成部分2高度相关的有针对性的高风险-高回报基础科学研究 聚集了整个生命周期内患有DS的大量个体，以进行深入的表型分析和研究 共存的条件。我们的目标是：1）通过表征抗肿瘤抗体， 患有DS的个体中的免疫景观与共同发生的自身免疫性疾病，然后与 免疫检查点抑制剂（ICI）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特征（组件1）;和2）扩展我们现有的DS 生物储存库，包括更多的成人和更多的个人与共同发生的自身免疫性疾病（组件 2）。所提出的研究的中心假设是，DS中的免疫特征促进了 自身免疫是保护实体瘤和促进治疗反应的相同免疫特征 ICI疗法。它是基于1）观察，与DS的人是保护发展实体瘤 也易患自身免疫; 2）越来越多的证据表明，治疗性免疫与自身免疫之间存在关联。 对ICI治疗的反应和自身免疫性irAE的发展。目标1的目标是增加 在我们现有的研究中，成年人的数量和同时发生自身免疫性疾病的个体数量 生物储藏室目标2的目标是通过识别共享的抗肿瘤标记物来定义最佳的抗肿瘤标记物。 DS患者和那些接受ICI治疗的患者之间的免疫结构特征， irAE。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和共同发生的自身免疫性甲状腺疾病的个体，然后与 发生ICI诱导的自身免疫性甲状腺炎。全球免疫格局将使用质量 流式细胞术和RNA测序。抗原特异性T细胞频率和表型将使用 通过测序的转录组和表位的激活诱导测定和单细胞细胞索引 （scCITE-seq）。这项工作将扩展抗肿瘤机制的理解，从而改善ICI 结果，并阐明了减轻DS患者自身免疫性而不减少抗- 肿瘤效应重要的是，它在母公司奖项的范围内，因为它专注于了解T细胞 ICI治疗后发生irAE的个体的反应。它还利用了专业知识和资源， 已经到位的父母补助金，并利用相同的方法和实验设计的父母 资助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.