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

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CD 8+细胞上表达。 肿瘤浸润淋巴细胞（TIL）表现出缺陷的效应子功能（细胞毒性和促炎性 细胞因子产生），因此是肿瘤清除的不良介质。在过去的十年中，免疫检查点 阻断剂（ICB）在许多癌症中实现了持久的反应，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。这些 观察结果强调了癌症治疗中尚未满足的临床需求，需要了解 构成对国际竞争性招标的有效回应，以提高回应率。 通过对ICB后CD 8 + TIL的群体和单细胞RNA谱的检查，我们已经确定了 干细胞样CD 8 + TIL是ICB应答的组成部分。这些细胞是肿瘤抗原特异性的， 多功能效应物能力，并且在不同癌症类型的各种ICB上比例增加。 虽然转录因子TCF-1在这些细胞的维持和效应功能中起重要作用， 我们发现，在所有的CD 8 + T细胞中，TCF-1的表达并不是ICB阳性反应的必要条件。 肿瘤背景。这些观察结果强调了干细胞样CD 8 + TILs对于有效应答肿瘤的相关性。 ICB和需要更好地了解TCF-1和其他因素如何调节其生物学。 干细胞驻留在小生境中，其中干细胞与小生境中的其他细胞之间的串扰不仅调节 它们的维持和功能，以及小生境细胞的功能。我们发现肿瘤相关的树突状细胞 当TCF-1在成熟的CD 8 + T细胞中不存在时，CD 8 + T细胞（DC）发生改变。因此，我们假设1）茎样 CD 8 + TIL位于肿瘤微环境（TME）中的小生境内，在那里它们与肿瘤微环境相互作用并调节肿瘤微环境。 抗原呈递细胞; 2）龛内的这种细胞间通讯回路可能是有效的抗原呈递细胞所必需的。 抗肿瘤T细胞应答的引发;和3）干细胞样CD 8 + TIL的调节可以积极或消极地影响免疫应答。 影响这一通信回路，从而影响ICB的功效。 我们的首要目标是了解干细胞样CD 8 + TIL的细胞自主调节， 与TME中其他细胞的串扰，以及它们如何共同控制熟练的抗- 肿瘤CD 8 + T细胞应答和ICB功效。因此，我们提出以下目标：1）确定 TCF-1在产生有效的抗肿瘤T细胞应答中的作用; 2）测试新的候选物TCF-1在产生有效的抗肿瘤T细胞应答中的作用。 干细胞样和效应细胞样CD 8 + TIL的调节子，和3）表征干细胞样CD 8 + TIL之间的串扰 和TME。

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.