Dissecting the enhancer logic governing immune cell fate decisions

项目摘要 CD 8 T细胞是有效抗肿瘤反应的关键组成部分。因此，癌症治疗的一个主要目标 免疫学，以及更广泛的免疫生物学， 控制T细胞的命运和功能。一个不断增长的，主要是描述性的染色质可及性图谱已经开始 为CD 8 T细胞的表观遗传景观提供了丰富的见解，但它仍然是一个挑战， 从这些数据中找出因果关系。此外，T细胞命运特化，像许多细胞 分化过程中，发展与连续的表型和功能的中间状态。这 提出了一个问题，哪些表观遗传机制是驱动CD 8 T细胞内状态转换的原因？ 驱动特定T细胞表型定型的最早信号通路是什么？如何 组织上下文形状抗肿瘤T细胞免疫？我们的建议通过利用损失来解决这些问题- 增强子编辑的功能获得（LOF）和功能获得（GOF）方法，以确定如何、何时以及在何处 CD 8 T细胞命运定型发生在体内。作为初始应用程序，我们将使用此框架来了解 背景特异性表观遗传机制控制肿瘤中耗尽的CD 8 T细胞分化 微环境我们特别关注比较黑色素瘤与黑色素瘤中祖细胞耗尽的T细胞。 肝细胞癌由于这两种疾病具有明显不同组织特异性信号传导， 对免疫检查点阻断的不同反应性，最重要的是，诱导共享和肿瘤- 表观遗传变化的特定模式。虽然这个项目将产生对T细胞的基本见解， 调控，我们还旨在将表观遗传重编程扩展到过继性T细胞治疗的临床前模型 具有潜在的治疗应用。实现这些目标的新技术集成有望 可用于CD 8 T细胞在癌症及其他疾病中发挥作用的各种疾病背景。

Project Summary CD8 T cells are a critical component of an effective anti-tumor response. Therefore, a major goal in cancer immunology, and more broadly in immunobiology, has been to understand how specific disease contexts govern T cell fate and function. A growing and largely descriptive atlas of chromatin accessibility has begun providing rich insight into the epigenetic landscape of CD8 T cells, yet it remains a challenge to understand cause-and-effect relationships from such data. Furthermore, T cell fate specification, like many cellular differentiation processes, develops with a continuum of phenotypic and functional intermediate states. This prompts the question, which epigenetic mechanisms are causal in driving state transitions within CD8 T cells? What are the earliest signaling pathways that drive commitment to particular T cell phenotype? How does tissue context shape anti-tumor T cell immunity? Our proposal addresses these questions by leveraging loss- of-function (LOF) and gain-of-function (GOF) approaches for enhancer editing to identify how, when and where CD8 T cell fate commitment happens in vivo. As an initial application, we will use this framework to understand the context-specific epigenetic mechanisms governing exhausted CD8 T cell differentiation in the tumor microenvironment. We focus in particular on comparing progenitor exhausted T cells in melanoma vs. hepatocellular carcinoma since these two diseases have markedly different tissue-specific signaling, have differential responsivity to immune checkpoint blockade, and most importantly, induce both shared and tumor- specific patterns of epigenetic changes. Although this project will yield fundamental insights into T cell regulation, we also aim to extend epigenetic reprogramming to preclinical models of adoptive T cell therapy with potential therapeutic application. The novel integration of technologies to achieve these goals promises to be useful for diverse disease contexts where CD8 T cells play a role, in cancer and beyond.