Differentiation and function of intratumoral memory-phenotype CD8+ T cells

瘤内记忆表型 CD8 T 细胞的分化和功能

基本信息

批准号：
10402376
负责人：
Peter Aidan Savage
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402376
关键词：
Adult Antigens Area Atypical lymphocyte Autoantigens Automobile Driving Biological Assay Biology CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cancer Patient Cell Differentiation process Cells Cues Data Dendritic Cells Development Differentiation Antigens Exhibits FOXP3 gene Gene Expression Profiling Goals Human Immune Immune response Immunologics Individual Infiltration Inflammatory Interferon Type II Knowledge Laboratories Ligands Malignant Neoplasms Malignant neoplasm of prostate Marker Discovery Memory Minor Molecular Mus Mutate Nature Oncogenes Peptides Phase Phenotype Play Population Process Production Property Prostatic Neoplasms Recurrence Regulatory T-Lymphocyte Reproducibility Research Role Signal Transduction Specificity Suggestion T memory cell T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Testing Thymus Gland Transplantation Tumor Antigens Tumor Immunity Tumor stage Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Up-Regulation Work anti-PD-1 base cancer cell cancer immunotherapy cancer type comparative density experience experimental study human disease immune checkpoint blockade insight interest melanoma mouse model novel novel marker pathogen programmed cell death protein 1 receptor response success thymocyte transcription factor transgenic adenocarcinoma of mouse prostate tumor

项目摘要

ABSTRACT While considerable evidence demonstrates that CD8+ TILs reactive to mutated or non-mutated tumor antigens play an important role in anti-tumor immunity, expanding evidence indicates that bona fide tumor-reactive T cells comprise only a minor fraction of all TILs in many human tumors, indicating that most CD8+ TILs have undefined specificity. Based on this long-standing question, we examined the hypothesis that a substantial fraction of TILs may represent CD8+ "memory-phenotype" T cells (CD8-MP cells), a unique population of cells of unknown antigen specificity that comprise 5-10% of CD8+ T cells in unprimed mice, exhibit common hallmarks of prior antigen experience, and have the capacity to rapidly expand and produce IFN-γ during an immune response. In preliminary work, we found that CD8-MP cells make substantial contributions to the immune infiltrate of oncogene-driven prostate tumors, and express high densities of the PD-1 inhibitory receptor. Given these unique insights, we embarked on parallel studies aimed at further elucidating the fundamental biology of CD8-MP cells, using a clonal approach to define the developmental trajectories of these cells. Our new data reveal that the differentiation of many CD8-MP clones is triggered by recognition of self-ligands in the thymus via a reproducible, orchestrated process, challenging current thought suggesting that CD8-MP cells differentiate in the periphery in response to homeostatic signals. In Aim 1, we will define the function of CD8-MP cells in anti-tumor immunity, testing the hypothesis that self-ligand recognition drives the early entry of CD8-MP cells into developing tumors, and that CD8-MP cells enhance anti-tumor immunity by catalyzing broader immune cell infiltration. In addition, we will identify novel markers that can be used to identify intratumoral CD8-MP cells, thereby enabling the broader study of CD8-MP cells in murine cancer models and human cancer patients. In Aim 2, we will elucidate the molecular and cellular mechanisms that direct CD8-MP differentiation, testing the hypothesis that CD8-MP differentiation is a two-step process triggered by TCR-dependent recognition of self-ligands presented by classical dendritic cells in the thymus. We will also utilize a unique T cell antigen discovery assay to identify natural self-peptides recognized by CD8-MP cells, thereby opening new areas of inquiry that were previously inaccessible. Ultimately, defining the function of intratumoral CD8-MP cells and the blueprints of CD8-MP differentiation in mice is expected to open new avenues for the study and manipulation of these cells in humans.

抽象的虽然有大量证据表明，CD8+ TILS对突变或未突变的肿瘤抗原反应在抗肿瘤免疫学中起重要作用，扩大证据表明真正的肿瘤反应性T 细胞在许多人类肿瘤中仅占所有TIL的一小部分，表明大多数CD8+ TIL具有未定义的特异性。基于这个长期存在的问题，我们研究了一个假设，即一个实质性的 TIL的一部分可能代表CD8+“存储 - 表型” T细胞（CD8-MP细胞），这是独特的细胞群未知的抗原特异性，占未植物小鼠中CD8+ T细胞的5-10％的特异性先前抗原经验的标志，并且具有在免疫反应。在初步工作中，我们发现CD8-MP细胞对癌基因驱动的前列腺肿瘤的免疫浸润，并表达PD-1抑制的高密度受体。鉴于这些独特的见解，我们进行了旨在进一步阐明的平行研究 CD8-MP细胞的基本生物学，采用克隆方法来定义这些细胞。我们的新数据表明，许多CD8-MP克隆的差异是通过识别的通过可重复的，精心策划的过程，胸腺中的自我配体挑战当前的思想表明 CD8-MP细胞响应稳态信号而在周围区分。在AIM 1中，我们将定义 CD8-MP细胞在抗肿瘤免疫中的功能，检验了自我识别驱动的假设 CD8-MP细胞的早期进入肿瘤，CD8-MP细胞通过催化更广泛的免疫细胞浸润。此外，我们将确定可以用来习惯的新颖标记识别肿瘤内CD8-MP细胞，从而实现了鼠类癌中CD8-MP细胞的更广泛研究模型和人类癌症患者。在AIM 2中，我们将阐明分子和细胞机制直接CD8-MP分化，检验了CD8-MP分化是两步过程的假设由TCR依赖性识别胸腺中经典树突状细胞提出的自我配体的识别引起的。我们还将利用独特的T细胞抗原发现测定法来识别CD8-MP识别的天然自肽细胞，从而打开了以前无法访问的新调查区域。最终，定义功能肿瘤内CD8-MP细胞和小鼠CD8-MP分化的蓝图有望打开新的研究和操纵这些细胞在人类中的途径。