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.

抽象的 CD8 T淋巴细胞是免疫系统消除癌症并病毒的主要机制 感染细胞。 CD8 T细胞通过识别显示在 MHC I分子。癌症和病毒可以通过抑制MHC I抗原表现来逃避免疫控制， CD8 T淋巴细胞更难检测和杀死这些病理细胞。因此，重要的是 了解调节抗原表现的机制以及肿瘤的机制 这些过程失调 - 这是该提案的总体目标。我们的建议基于我们的发现 四叠蛋白酶（TSPAN5）的无偏向前遗传筛选，该筛选意外地组织了MHC I分子 放大剧院刺激CD8 T细胞反应能力的方式。我们的第一个目标将阐明基础 这种生物学作用的分子机制。这个目标将检验TSPAN5组织MHC I的假设 分子成刺激膜微区 其他关键配体显着提高了抗原表现的效率。我们的第二个目标将阐明如何，何时 以及tspan5-mHC I微区域形成的位置。这个目标将检验肽-MHC I配合物的假设 从肽加载络合物释放后，被掺入TSPAN5免疫刺激性微区 在ER中，通过与TSPAN5和其他TSPAN家族成员的特定分子相互作用，然后 免疫刺激微区域被贩运到质膜上并保持在质膜上以进行显示。我们的第三 目的是基于我们的发现，即某些癌症（包括肾细胞癌）显着下调 TSPAN 5表达。我们第三个目标的基础假设是，TSPAN5的这种表达丧失是 癌症逃避免疫监视和控制的方式，从而进步。该假设的必然 是TSPAN5的丧失是一种会影响对免疫疗法的耐药性的机制；因此，tspan5可以 提供急需的生物标志物，用于识别不会对免疫疗法反应的患者，也可以 成为恢复对这种治疗反应的潜在治疗靶标。我们的实验方法将使用 在临床前模型中 人性化和野生型小鼠定义TSPAN5在肿瘤免疫逃避和对 对人和小鼠肿瘤的检查点阻塞的免疫疗法。最后，我们将翻译这些 通过研究TSPAN5表达是否是一种可以预测的生物标志物，对人类癌症患者的发现 临床课程。我们提出的实验的假设和可行性由强烈的初步支持 数据。综上所述，我们提出的实验将来自基本的机械研究，这将阐明 具有优化APC刺激T细胞反应能力的能力的潜在基本和新颖机制 临床前和临床研究将定义这种机制的丧失如何影响癌症的免疫控制 和临床结果。