Role of Tspan5 in MHC I antigen presentation and cancer immune evasion

Tspan5 在 MHC I 抗原呈递和癌症免疫逃避中的作用

• 批准号: 10584551
• 负责人: KENNETH L ROCK
• 金额: $ 49.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584551
• 关键词: Abbreviations; Affect; Antigen Presentation; Antigen-Presenting Cells; Atomic Force Microscopy; Binding; Biological; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Control; Cancer Patient; Cell membrane; Cells; Cessation of life; Clinical; Clinical Research; Complex; Cross Presentation; Data; Dendritic Cells; Disease; Electron Microscopy; Endoplasmic Reticulum; Exclusion; Family member; Formalin; Genetic Screening; Goals; Hemagglutinin; Host Defense; Human; I-antigen; Immune; Immune Evasion; Immune response; Immune system; Immunohistochemistry; Immunologic Surveillance; Immunoprecipitation; Immunotherapy; Kinetics; Ligands; MHC Class II Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Membrane Microdomains; Modeling; Molecular; Mus; Outcome; Paraffin Embedding; Pathologic; Patients; Peptide/MHC Complex; Peptides; Physiology; Pre-Clinical Model; Process; Regulation; Renal Cell Carcinoma; Resistance; Role; Scanning; Signal Transduction; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Time; Transcript; Translating; Tumor Escape; Viral; Virus; Western Blotting; Wild Type Mouse; cancer immunotherapy; clinical predictors; clinical translation; cohort; density; experimental study; fighting; gain of function; immune checkpoint blockade; immune clearance; immunogenic; improved; inhibitor; insight; loss of function; novel; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; therapeutic target; treatment and outcome; tumor

Abstract CD8 T lymphocytes are the major mechanism by which the immune system eliminates cancers and virally infected cells. CD8 T cells detect these abnormal targets by recognizing immunogenic peptides displayed on MHC I molecules. Cancers and viruses can evade immune control by inhibiting MHC I antigen presentation, making it harder for CD8 T lymphocytes to detect and kill these pathological cells. Therefore, it is important to understand the mechanisms that regulate antigen presentation as well as the mechanisms by which tumors dysregulate these processes - this is the overall goal of this proposal. Our proposal is based on our discovery in an unbiased forward genetic screen of a Tetraspanin (Tspan5) that unexpectedly organizes MHC I molecules in ways that amplify theair ability to stimulate CD8 T cell responses. Our 1st aim will elucidate the underlying molecular mechanisms for this biological effect. This Aim will test the hypothesis that Tspan5 organizes MHC I molecules into stimulatory membrane microdomains that by virtue of size, MHC I density and/or incorporation of other key ligands markedly increases the efficiency of antigen presentation. Our 2nd aim will elucidate how, when and where Tspan5-MHC I microdomains form. This aim will test the hypotheses that peptide-MHC I complexes are incorporated into Tspan5 immunostimulatory microdomains upon release from the peptide-loading complex in the ER, through specific molecular interactions with Tspan5 and other Tspan family members, and then these immunostimulatory microdomains are trafficked to and maintained on the plasma membrane for display. Our 3rd Aim is based on our finding that certain cancers, including renal cell carcinomas, significantly downregulate Tspan 5 expression. The hypothesis underlying our 3rd Aim is that this loss of expression of Tspan5 is one of the ways that cancers escape immune surveillance and control and thereby progress. A corollary of this hypothesis is that the loss of Tspan5 is a mechanism that will influence resistance to immunotherapy; as such, Tspan5 could provide a much-needed biomarker for identifying patients who will not respond to immunotherapy and could also be a potential therapeutic target to restore responses to such therapy. Our experimental approach will use isogenic Tspan5-edited renal cell cancers (loss of function and gain of function) in preclinical models with humanized and wild type mice to define the role of Tspan5 in tumor immune evasion and responsiveness to immunotherapy with checkpoint blockade for both human and mouse tumors. Finally, we will translate these findings into human cancer patients by investigating whether Tspan5 expression is a biomarker that can predict clinical course. Our hypotheses and feasibility of the proposed experiments are supported by strong preliminary data. Taken together, our proposed experiments will go from basic mechanistic studies, which will elucidate a potentially fundamental and novel mechanism for optimizing the ability of APCs to stimulate T cell responses, to preclinical and clinical studies, which will define how loss of this mechanism affects immune control of cancers and clinical outcomes.

摘要 CD 8 T淋巴细胞是免疫系统消除癌症和病毒的主要机制。 被感染的细胞CD 8 T细胞通过识别细胞表面上展示的免疫原性肽来检测这些异常靶标。 MHC I分子。癌症和病毒可以通过抑制MHC I抗原呈递来逃避免疫控制， 这使得CD 8 T淋巴细胞更难检测和杀死这些病理细胞。因此， 了解调节抗原呈递的机制以及肿瘤 使这些过程失去控制----这是本提案的总体目标。我们的建议是基于我们在 一种四跨膜蛋白（Tspan 5）的无偏正向遗传筛选，它意外地组织了MHC I分子， 增强空气刺激CD 8 T细胞反应的能力。我们的第一个目标将阐明 这种生物效应的分子机制。本研究旨在验证Tspan 5组织MHC I的假设 分子进入刺激性膜微区，所述微区凭借大小、MHC I密度和/或MHC I分子的掺入， 其它关键配体显著增加抗原呈递的效率。我们的第二个目标将阐明如何，当 以及Tspan 5-MHCI微区形成的位置。这一目的将检验肽-MHC I复合物 在从肽负载复合物释放时掺入Tspan 5免疫刺激微结构域 在ER中，通过与Tspan 5和其他Tspan家族成员的特异性分子相互作用，然后这些 免疫刺激微结构域被运输到质膜并保持在质膜上用于展示。我们的第三个 目的是基于我们的发现，某些癌症，包括肾细胞癌， Tspan 5表达。我们的第三个目标的假设是Tspan 5表达的缺失是导致细胞凋亡的原因之一。 癌症逃避免疫监视和控制从而发展的方式。这个假设的推论 Tspan 5的缺失是一种影响免疫治疗抗性的机制;因此，Tspan 5可能 提供了一种急需的生物标志物，用于识别对免疫治疗无反应的患者， 是恢复对这种治疗的反应的潜在治疗靶点。我们的实验方法将使用 临床前模型中的同基因Tspan 5编辑的肾细胞癌（功能丧失和功能获得）， 人源化和野生型小鼠，以确定Tspan 5在肿瘤免疫逃避和对肿瘤免疫应答中的作用。 免疫治疗与检查点阻断用于人类和小鼠肿瘤。最后，我们将这些 通过研究Tspan 5表达是否是一种可以预测癌症的生物标志物， 临床过程我们的假设和建议的实验的可行性是支持强初步 数据总之，我们提出的实验将从基本的机理研究，这将阐明一个 优化APC刺激T细胞应答的能力的潜在基础和新机制， 临床前和临床研究，将确定这种机制的丧失如何影响癌症的免疫控制 临床结果。