Specificity and function of memory-phenotype CD8+ T cells in the tumor environment

项目摘要/摘要 经典的说法是，记忆T细胞是在外围对外来病原体产生有效免疫反应后产生的， 并准备对反复的病原体挑战做出更快的反应。然而，在从来没有 遇到外来病原体时，有一个主要的内源性CD8+T细胞亚群表达表型 免疫记忆标志物，占外周CD8+T细胞总数的10-20%。尽管盛行 在这种“记忆表型”CD8+T细胞(CD8-MP)群体中，由这些细胞识别的抗原的性质 细胞及其发育的解剖部位仍未完全确定。之前的工作是 仅限于对可能表现出表型和功能的大量多克隆CD8-MP细胞群体的研究 异质性。这项建议旨在阐明CD8-MP细胞生物学的基本方面 克隆水平。使用一种独特的克隆方法，这项工作试图阐明来源，抗原特异性，和 CD8-MP细胞在稳态和癌基因驱动的前列腺癌背景下的功能。中环 这一设想的假设是，外周内源性自身配体的TCR识别驱动了 CD8-MP克隆的分化及其在小鼠前列腺中的选择性募集 肿瘤。目标1中的研究将确定TCR驱动CD8-MP分化的程度 识别内源性自身配体并阐明胸腺是否存在CD8-MP分化 或者在外围。这些研究有望证明很大一部分CD8-MP细胞表达 TCR识别外周经典MHC-I类分子呈现的自我配体，驱动 分化为CD8-MP亚群。目标2中的研究将确定CD8-MP细胞的贡献 肿瘤浸润性淋巴细胞池，测定CD8-MP细胞对TRAMP功能的影响 前列腺癌。预计CD8-MP克隆型在前列腺癌中占相当大的比例- 渗入CD8+T细胞，提示CD8-MP T细胞对非突变自身配体的反应可能在 在肿瘤环境中发挥独特的功能作用。这样的证据将有助于解释一个长期存在的难题 在肿瘤免疫学中，T细胞对肿瘤表达的新抗原、分化抗原或 在人类原发肿瘤中可以检测到癌症睾丸抗原，但通常很少见，这表明 大多数肿瘤浸润性T细胞具有未知的特异性。最终，理解这一现象的生物学原理 处于动态平衡和肿瘤微环境中的显著CD8+细胞亚群将提供独特的见解 用于未来的临床前研究，旨在操纵自体CD8-MP细胞以获得治疗益处。

PROJECT SUMMARY/ ABSTRACT Classically, memory T cells arise after a productive immune response to a foreign pathogen in the periphery, and are poised to respond more rapidly to repeated pathogen challenge. However, in mice that have never encountered foreign pathogens, there is a major subset of endogenous CD8+ T cells that express phenotypic markers of immunological memory, making up 10-20% of total peripheral CD8+ T cells. Despite the prevalence of this “memory phenotype” CD8+ T cell (CD8-MP) population, the nature of the antigens recognized by these cells and the anatomical sites in which they develop remain incompletely defined. Previous work has been limited to the study of bulk polyclonal CD8-MP cell populations, which may exhibit phenotypic and functional heterogeneity. This proposal seeks to elucidate fundamental aspects of the biology of CD8-MP cells at the clonal level. Using a unique clonal approach, this work seeks to elucidate the origin, antigen specificity, and function of CD8-MP cells at steady state and in the context of oncogene-driven prostate tumors. The central hypothesis of this proposal is that TCR recognition of endogenous self-ligands in the periphery drives the differentiation of CD8-MP clones, as well as the selective recruitment of these clonotypes into murine prostate tumors. The studies in Aim 1 will determine the extent to which CD8-MP differentiation is driven by TCR recognition of endogenous self-ligands and to elucidate whether CD8-MP differentiation occurs in the thymus or in the periphery. These studies are expected to demonstrate that a large fraction of CD8-MP cells express TCRs that recognize self-ligands presented by classical MHC class-I molecules in the periphery, which drives their differentiation into the CD8-MP subset. The studies in Aim 2 will define the contribution of CD8-MP cells to the pool of tumor-infiltrating lymphocytes and determine the functional impact of CD8-MP cells on TRAMP prostate tumors. It is anticipated that CD8-MP clonotypes make up a substantial fraction of prostate tumor- infiltrating CD8+ T cells, suggesting that CD8-MP T cells reactive to non-mutated self-ligands may play a unique functional role in the tumor environment. Such evidence would help explain a long-standing conundrum in tumor immunology, in which T cells reactive to tumor-expressed neo-antigens, differentiation antigens, or cancer testis antigens can be detected in primary human tumors but are typically rare, indicating that the majority of tumor-infiltrating T cells have undefined specificities. Ultimately, understanding the biology of this prominent subset of CD8+ cells at homeostasis and in the tumor microenvironment will provide unique insight for future preclinical studies aimed at manipulating autologous CD8-MP cells for therapeutic benefit.