Regulation of stem-like CD8+ T cells and their role in immunotherapy

干细胞样 CD8 T 细胞的调节及其在免疫治疗中的作用

• 批准号: 10211084
• 负责人: ANA C ANDERSON
• 金额: $ 41.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211084
• 关键词: Affect; Antigen-Presenting Cells; Antitumor Response; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Patient; Cell Communication; Cell physiology; Cells; Clinical; Communication; Data; Dendritic Cells; Exhibits; Generations; Genes; Genomics; Goals; Human; Immune; Immunotherapy; Inflammatory; Knockout Mice; Knowledge; Licensing; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Memory; Modification; Morbidity - disease rate; Mus; Outcome; Patients; Phenotype; Play; Population; Positioning Attribute; Production; RNA; Regulation; Renal carcinoma; Reporter; Reporting; Role; Sampling; T cell response; T-Lymphocyte; TCF Transcription Factor; Technology; Testing; Tumor Antigens; Tumor Tissue; Tumor-Infiltrating Lymphocytes; cancer therapy; cancer type; checkpoint receptors; cytokine; cytotoxicity; exhaust; genome editing; immune checkpoint; immune checkpoint blockade; improved; intercellular communication; loss of function; melanoma; mortality; neoplastic cell; novel; programmed cell death protein 1; receptor expression; response; stem; stem cells; success; tool; transcriptomics; tumor; tumor microenvironment

PROJECT SUMMARY Immune checkpoint receptors (e.g. CTLA-4, PD-1, Tim-3) are expressed on dysfunctional or “exhausted” CD8+ tumor-infiltrating lymphocytes (TILs) that exhibit defective effector functions (cytotoxicity and pro-inflammatory cytokine production) and are thus poor mediators of tumor clearance. In the last decade, immune checkpoint blockade (ICB) has achieved durable responses in many cancers, including melanoma, lung, and renal cancer. Despite this success, current estimates indicate that only 12% of all cancer patients respond to ICB. These observations underscore the remaining unmet clinical need in cancer treatment and the need to understand what constitutes effective response to ICB in order to improve response rates. Through examination of the population and single-cell RNA profiles of CD8+ TILs upon ICB, we have identified stem-like CD8+ TILs that are integral for the response to ICB. These cells are tumor antigen-specific, exhibit polyfunctional effector capacity, and increase in proportion upon various ICBs across different cancer types. Although the transcription factor TCF-1 plays an important role in the maintenance and effector function of these cells, we have found that TCF-1 expression in CD8+ T cells is not requisite for positive response to ICB in all tumor contexts. These observations underscore the relevance of stem-like CD8+ TILs for effective response to ICB and the need to better understand how TCF-1 and additional factors regulate their biology. Stem cells reside in niches where crosstalk between stem cells and other cells in the niche regulates not only their maintenance and function but also the function of niche cells. We have found that tumor-associated dendritic cells (DCs) are altered when TCF-1 is absent in mature CD8+ T cells. We thus hypothesize that 1) stem-like CD8+ TILs reside within niches in the tumor micro-environment (TME) where they interact with and modulate antigen-presenting cells; 2) this intercellular communication circuit within the niche may be required for effective priming of anti-tumor T cell responses; and 3) modulation of stem-like CD8+ TILs may positively or negatively influence this communication circuit, thus affecting the efficacy of ICB. Our overarching goal is to understand the cell-autonomous regulation of stem-like CD8+ TILs, their crosstalk with other cells in the TME, and how together they govern the activation of proficient anti- tumor CD8+ T cell responses and ICB efficacy. Accordingly, we propose the following aims: 1) Determine the role of TCF-1 in the generation of proficient anti-tumor T cell responses; 2) Test the role of novel candidate regulators of stem- and effector-like CD8+ TILs, and 3) Characterize the crosstalk between stem-like CD8+ TILs and the TME.

项目摘要 免疫检查点受体（例如CTLA-4，PD-1，TIM-3）在功能失调或“耗尽”的CD8+上表达 暴露有缺陷效应子功能的肿瘤浸润淋巴细胞（TIL）（细胞毒性和促炎性） 细胞因子的产生），因此是肿瘤清除率较差的介质。在过去的十年中，免疫检查站 在包括黑色素瘤，肺癌和肾癌在内的许多癌症中，块glocade（ICB）已经达到了持久的反应。 尽管取得了成功，但目前的估计表明，所有癌症患者中只有12％对ICB做出反应。这些 观察结果强调了癌症治疗中剩余的未满足的临床需求，并且需要了解什么 构成对ICB的有效反应，以提高响应率。 通过检查冰上CD8+ TIL的种群和单细胞RNA曲线，我们已经确定了 茎状的CD8+ TIL是对ICB响应的组成部分。这些细胞是肿瘤抗原特异性的 多功能效应子的能力，并增加了不同癌症类型的各种ICB的比例。 尽管转录因子TCF-1在维护和效应子功能中起重要作用 细胞，我们发现CD8+ T细胞中的TCF-1表达并不是所有人对ICB的阳性反应的必要条件 肿瘤环境。这些观察结果强调了茎样CD8+ TIL的相关性，以有效响应 ICB以及更好地了解TCF-1和其他因素如何调节其生物学的需求。 干细胞驻留在壁ches中，其中干细胞与小裂细胞之间的串扰不仅可以调节 它们的维护和功能，也是利基细胞的功能。我们发现与肿瘤相关的树突状 当成熟的CD8+ T细胞中不存在TCF-1时，细胞（DC）会改变。因此，我们假设1）类似茎状 CD8+ TILS位于肿瘤微环境（TME）中的壁ni中 抗原呈递细胞； 2）在利基内可能需要此细胞间通信电路才能有效 抗肿瘤T细胞反应的启动； 3）茎状CD8+ TIL的调节可能会积极或负面 影响该通信电路，从而影响ICB的效率。 我们的总体目标是了解茎状CD8+ TIL的细胞自主调节，它们 与TME中的其他细胞串扰，以及它们如何共同控制熟练的抗抗激活 肿瘤CD8+ T细胞反应和ICB效率。根据，我们提出以下目的：1）确定 TCF-1在熟练的抗肿瘤T细胞反应的产生中的作用； 2）测试新候选人的作用 茎状的和效应器状的CD8+ TIL的调节剂，以及3）表征茎状CD8+ TIL之间的串扰 和TME。