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

基本信息

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
项目类别：
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

项目摘要

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和病毒的主要机制被感染的细胞。 CD8 T 细胞通过识别上显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，使 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呈递的机制以及肿瘤的机制失调这些过程——这是该提案的总体目标。我们的建议是基于我们的发现对四跨膜蛋白 (Tspan5) 进行无偏见的正向遗传筛选，该蛋白意外地将 MHC I 分子组织在增强空气刺激 CD8 T 细胞反应能力的方法。我们的第一个目标将阐明根本原因这种生物效应的分子机制。该目标将检验 Tspan5 组织 MHC I 的假设分子进入刺激膜微域，其大小、MHC I 密度和/或掺入其他关键配体显着提高了抗原呈递的效率。我们的第二个目标将阐明如何、何时以及 Tspan5-MHC I 微结构域形成的地方。该目标将检验肽-MHC I 复合物的假设从肽负载复合物中释放后，被整合到 Tspan5 免疫刺激微结构域中在 ER 中，通过与 Tspan5 和其他 Tspan 家族成员的特定分子相互作用，然后这些免疫刺激微结构域被运输并维持在质膜上以进行展示。我们的第三个目标基于我们的发现，即某些癌症，包括肾细胞癌，显着下调 Tspan 5 表达。我们的第三个目标的假设是 Tspan5 表达的丧失是其中之一癌症逃避免疫监视和控制从而进展的方式。这个假设的推论 Tspan5 的缺失是一种影响免疫治疗耐药性的机制；因此，Tspan5 可以提供急需的生物标志物，用于识别对免疫疗法没有反应的患者，也可以成为恢复对此类疗法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同基因 Tspan5 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 Tspan5 在肿瘤免疫逃避和反应性中的作用针对人类和小鼠肿瘤的检查点阻断免疫疗法。最后，我们将翻译这些通过调查 Tspan5 表达是否是可以预测的生物标志物，对人类癌症患者进行了研究临床过程。我们的假设和所提出的实验的可行性得到了强有力的初步支持数据。总而言之，我们提出的实验将从基本机制研究开始，这将阐明优化 APC 刺激 T 细胞反应能力的潜在基础和新颖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和临床结果。