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: 10400137
• 负责人: ANA C ANDERSON
• 金额: $ 40.34万
• 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/10400137
• 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; treatment response; 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.

项目概要 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 表现出有缺陷的效应功能（细胞毒性和促炎性）的肿瘤浸润淋巴细胞（TIL） 细胞因子的产生），因此是肿瘤清除的不良介质。在过去的十年中，免疫检查点。 阻断（ICB）已在许多癌症中取得了持久的缓解，包括黑色素瘤、肺癌和肾癌。 尽管取得了这一成功，但目前的估计表明，只有 12% 的癌症患者对 ICB 有反应。 观察强调了癌症治疗中剩余的未满足的临床需求以及需要了解什么 构成对 ICB 的有效应对，以提高应对率。 通过检查 ICB 上 CD8+ TIL 的群体和单细胞 RNA 谱，我们发现 干细胞样 CD8+ TIL 是 ICB 反应不可或缺的一部分，这些细胞具有肿瘤抗原特异性。 多功能效应器能力，并且在不同癌症类型的各种 ICB 上按比例增加。 尽管转录因子TCF-1在这些细胞的维持和效应功能中发挥着重要作用。 细胞中，我们发现 CD8+ T 细胞中的 TCF-1 表达并不是所有 ICB 阳性反应所必需的。 这些观察结果强调了干细胞样 CD8+ TIL 与有效应对肿瘤的相关性。 ICB 以及更好地了解 TCF-1 和其他因子如何调节其生物学的需要。 干细胞驻留在微环境中，干细胞与微环境中其他细胞之间的串扰不仅调节 它们的维护和功能还与肿瘤相关的树突状细胞的功能有关。 当成熟 CD8+ T 细胞中缺乏 TCF-1 时，细胞 (DC) 就会发生改变，因此我们追求 1) 干细胞样。 CD8+ TIL 存在于肿瘤微环境 (TME) 的微环境中，在那里它们相互作用并进行调节 抗原呈递细胞；2) 微环境内的这种细胞间通讯回路可能是有效的所必需的。 抗肿瘤 T 细胞反应的启动；3) 干细胞样 CD8+ TIL 的调节可能是阳性的，也可能是阴性的 影响该通讯电路，从而影响ICB的功效。 我们的首要目标是了解干细胞样 CD8+ TIL 的细胞自主调节、它们的 与 TME 中其他细胞的串扰，以及它们如何共同控制有效抗-细胞因子的激活 肿瘤 CD8+ T 细胞反应和 ICB 疗效因此，我们提出以下目标： 1) 确定 TCF-1 在产生高效抗肿瘤 T 细胞反应中的作用 2) 测试新候选物的作用； 干细胞和效应细胞样 CD8+ TIL 的调节因子，以及 3) 表征干细胞样 CD8+ TIL 之间的串扰 和 TME。