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

项目总结 免疫检查点受体(如CTLA-4、PD-1、TIM-3)在功能障碍或“衰竭”的CD8+细胞上表达 肿瘤浸润性淋巴细胞(TIL)表现出效应器功能缺陷(细胞毒性和促炎作用 细胞因子的产生)，因此是肿瘤清除的不良介体。在过去的十年里，免疫检查站 BLOKADE(ICB)在许多癌症中取得了持久的疗效，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，所有癌症患者中只有12%对ICB有反应。这些 观察结果强调了癌症治疗中仍未得到满足的临床需求，以及了解 构成对ICB的有效回应，以提高应答率。 通过对ICB上CD8+TIL的群体和单细胞RNA图谱的检测，我们发现 干细胞样CD8+TIL对ICB的应答是不可或缺的。这些细胞是肿瘤抗原特异性的，表现为 多功能效应器能力，并在不同癌症类型的不同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起着重要作用 细胞，我们发现CD8+T细胞中TCF-1的表达不是ICB阳性反应所必需的 肿瘤相关知识。这些观察结果强调了干细胞样CD8+TIL与有效应答的相关性 ICB以及更好地了解TCF-1和其他因子如何调节它们的生物学的必要性。 干细胞驻留在壁龛中，干细胞和壁龛中其他细胞之间的串扰不仅调节 它们的维持和功能还包括壁龛细胞的功能。我们发现肿瘤相关的树突状细胞 当成熟的CD8+T细胞中缺少TCF-1时，细胞(DC)发生改变。因此，我们假设茎状结构 CD8+TIL驻留在肿瘤微环境(TME)的小生境中，它们在那里与之相互作用并进行调节 抗原提呈细胞；2)壁龛内的这种细胞间通讯回路可能是有效的 抗肿瘤T细胞反应的启动；以及3)干细胞样CD8+TIL的调节可能是积极的，也可能是消极的 影响这一通信线路，从而影响ICB的疗效。 我们的首要目标是了解干细胞样CD8+TIL的细胞自主调节，他们的 与TME中其他细胞的串扰，以及它们如何共同管理熟练的反- 肿瘤CD8+T细胞应答与ICB疗效据此，我们提出了以下目标：1)确定 TCF-1在产生熟练的抗肿瘤T细胞反应中的作用；2)测试新候选者的作用 干样和效应型CD8+TIL的调节，以及3)干样CD8+TIL之间的串扰特征 还有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.