(PQ3) Disruption of immune surveillance by aneuploidy and aberrant MHCII expression

(PQ3) 非整倍体和异常 MHCII 表达破坏免疫监视

• 批准号: 9379383
• 负责人: Hannah Kathryn Carter
• 金额: $ 31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379383
• 关键词: Address; Aftercare; Aneuploidy; Antigens; B-Lymphocytes; Cancer Center; Cancer Control; Cancer Patient; Cell physiology; Cells; Cellular biology; Characteristics; Chemicals; Chromosome abnormality; Clinical; Clonality; Complex; Consensus; Data; Dendritic Cells; Failure; Funding Opportunities; Genomics; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunologics; Immunotherapy; Impairment; In Vitro; Individual; Infiltration; Inflammatory; Intervention; Light; Link; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Mediating; Molecular Chaperones; Mus; Myeloid Cells; Natural Killer Cells; Outcome; Patients; Pharmacology; Phenotype; Play; Population; Proxy; Publishing; Regulation; Research; Role; Sampling; Stress; T-Lymphocyte; Testing; The Cancer Genome Atlas; Tissues; Tumor Immunity; Validation; arm; base; cancer cell; cancer genomics; clinical predictors; design; experimental study; high risk; immune checkpoint blockade; immune function; in vivo; lens; macrophage; patient oriented; patient population; patient stratification; peripheral blood; predictive signature; prognostic; proteotoxicity; repository; response; survival prediction; tauroursodeoxycholic acid; transcriptome sequencing; tumor; tumor microenvironment

This new R01 application is submitted in response to Funding Opportunity RFA-CA-15-008 “Research Answers to NCI's Provocative Questions”. The hypothesis to be tested is in response to PQ3. We hypothesize that the benefit afforded by immune surveillance to the individual and populations of cancer patients may depend on the levels of aneuploidy and expression of the Major Histocompatibility Complex (MHC) complex Class II (MHCII) in the tumor. We further predict that a population of individuals defined by tumors with high aneuploidy and low MHCII expression is at higher risk of progression and poor outcome, and unresponsiveness to immunotherapy by regulating the size and composition of intra-tumor immune infiltrates. Within this new paradigm, we also propose to investigate the possible causative mechanism of aneuploidy- induced proteotoxic stress. The study will be a combination of genomic analyses and immunological interrogation in UCSD Moores Cancer Center patients, and will ultimately seek validation in through TCGA data as well as data from immunotherapy trials. We propose four Aims. (1) To validate aneuploidy/MHC II as predictors of progression and clinical outcome. TCGA data will be interrogated to relate an association between aneuploidy and levels of MHCII expression to overall survival. and response in immunotherapy (ICPi) trials. (2) To measure markers of natural immune response in cancer patients grouped according to aneuploidy/MHC II status. We will study the size and clonality of tumor-infiltrating T cells by profiling TCR reactive with TERT, an antigen expressed by cancer cells at every stage of differentiation, as a proxy of the autochthonous anti-cancer response. By comparing tumor-infiltrating T cells to circulating T cells, we expect to determine if (a) tumor the aneuploidy/MHCII signature predicts T cell infiltration, and (b) lower immune T cell infiltration displays high TCR heterogeneity. (3) To determine whether aneuploidy/MHCII status interferes with response to ICPi therapy. We will determine if high aneuploidy/low MHCII expression impairs immune reactivation after ICPi therapy, and use immunoscore from responder and nonresponder patients. (4) To determine whether proteotoxic stress is the mechanism by which aneuploidy interferes with immune response. Because aneuploidy induces proteotoxic stress, the ensuing UPR provides a mechanistic link between cancer cell biology and immune surveillance. In vitro and in vivo experiments using cells with pharmacologically-induced aneuploidy will be used to determine the extent to which UPR cell nonautonomous effects may account for a disruption of local immunity, i.e., number and characteristics of tumor infiltrating myeloid cells. We believe that an analysis at the interface between cancer genomic and immune surveillance may reveal general rules for immune-mediated control of cancer. This may help stratify patients and their clinical trajectory, and predict clinical responses to immunotherapy more accurately. !

这项新的 R01 申请是为了响应资助机会 RFA-CA-15-008“研究 NCI 挑衅性问题的答案”。要测试的假设是对 PQ3 的回应。我们假设 免疫监测给癌症患者个体和群体带来的好处可能 取决于非整倍体水平和主要组织相容性复合物 (MHC) 复合物的表达 肿瘤中的 II 类 (MHCII)。我们进一步预测，由高肿瘤定义的个体群体 非整倍体和低 MHCII 表达存在较高的进展风险和不良结果，并且 通过调节肿瘤内免疫浸润的大小和组成来对免疫治疗无反应。 在这个新范式中，我们还建议研究非整倍体的可能致病机制 诱导的蛋白毒性应激。该研究将基因组分析和免疫学分析相结合 对 UCSD Moores 癌症中心患者进行询问，最终将通过 TCGA 寻求验证 数据以及免疫治疗试验的数据。我们提出四个目标。 (1) 验证非整倍性/MHC II 作为进展和临床结果的预测因子。 TCGA 数据将是 探讨非整倍性和 MHCII 表达水平与总生存率之间的关联。 和免疫治疗（ICPi）试验中的反应。 (2) 测量自然免疫反应的标志物 根据非整倍体/MHC II 状态对癌症患者进行分组。我们将研究其大小和克隆性 通过分析与 TERT（癌细胞在每个时间段表达的抗原）反应的 TCR 来分析肿瘤浸润 T 细胞 分化阶段，作为本地抗癌反应的代表。通过比较肿瘤浸润 T 细胞到循环 T 细胞，我们希望确定 (a) 肿瘤非整倍性/MHCII 特征是否预测 T 细胞 (b) 较低的免疫 T 细胞浸润表现出较高的 TCR 异质性。 (3)判断是否 非整倍体/MHCII 状态会干扰 ICPi 治疗的反应。我们将确定高非整倍性/低非整倍性 MHCII 表达会损害 ICPi 治疗后的免疫再激活，并使用应答者和患者的免疫评分 无反应患者。 (4) 确定蛋白毒性应激是否是其机制 非整倍体会干扰免疫反应。因为非整倍体会引起蛋白毒性应激，随之而来的 UPR 提供了癌细胞生物学和免疫监视之间的机制联系。体外和体内 使用具有药物诱导的非整倍性的细胞进行的实验将用于确定非整倍性的程度 UPR 细胞非自主效应可能会导致局部免疫的破坏，即数量和 肿瘤浸润骨髓细胞的特征。 我们相信，对癌症基因组和免疫监视之间的界面进行分析可能会 揭示免疫介导的癌症控制的一般规则。这可能有助于对患者及其临床情况进行分层 轨迹，并更准确地预测免疫治疗的临床反应。 ！