Reprogramming tumor-reactive CD8 T cells by targeting the IL-21-BATF pathway to treat melanoma

项目摘要 晚期黑色素瘤是癌症免疫治疗研究的主要靶点，因为它的存活率甚至很低 随着最近的治疗进展。目前的策略主要集中在CD8 T细胞进入功能障碍状态 肿瘤微环境。最近的研究发现，肿瘤内的CD8T细胞由一个 表现为记忆样祖细胞、效应细胞和终末耗尽细胞的异质性群体 不同的职能和自我更新能力。然而，细胞和分子过程中涉及的 黑色素瘤中这些亚群的区别还不是很清楚。探索CD8 T细胞的复杂性 向效应器图谱的分化可以识别新的免疫治疗靶点。因此，从长远来看， 本项目的目的是阐明调节效应分子CD8T细胞分化和 在黑色素瘤中起作用。 CD4T细胞产生的细胞因子为CD8T细胞提供帮助。最近的研究发现了细胞因子IL-1。 21作为CD4T细胞产生的关键信号，帮助促进CD8T细胞在慢性感染中的维持。 然而，CD4T细胞产生的IL-21对CD8T细胞分化和功能的直接影响 癌症仍是未知数。该提案中提供的初步数据表明，产生IL-21的CD4T细胞 诱导依赖CD8 T细胞的有效抗肿瘤反应。此外，它之前已经被发现 IL-21信号诱导转录因子BATF与IRF4协同结合 引起染色质景观的变化。这导致了IL-21-BATF途径的假设 BATF-IRF4增强黑色素瘤浸润性效应细胞CX3CR1+CD8T细胞及其功能 介导的转录调控。 AIM 1将确定过继转移产生IL-21的CD4T细胞是否增强效应器CX3CR1+ CD8T细胞分化。CD4T细胞来源的IL-21对CD8T细胞分化和功能的影响 在体内被确定。然后，将确定IL-21R信号是否对CD8T细胞是内在必需的 对IL-21产生的CD4T细胞的反应有帮助。 目的2探讨BATF介导的肿瘤浸润性CD8 T细胞分化的机制。 这些实验将确定是否需要BATF-IRF4相互作用来促进肿瘤浸润性CX3CR1+ CD8T细胞。此外，BATF介导的染色质可及性在CD8T细胞分化和 将对功能进行评估。 这一建议将有助于理解CD8T细胞在黑色素瘤中的分化和功能。这是在排队的 NCI的使命，因为这个项目的结果可能导致BATF作为一个新的 促进效应CD8 T细胞分化抗癌的治疗机制。

Project Summary Advanced melanoma is a major target of cancer immunotherapy research due to its poor survival rate even with recent treatment advances. Current strategies focus on CD8 T cells which enter a dysfunctional state in the tumor microenvironment. Recent studies have found that intratumoral CD8 T cells consist of a heterogeneous population of memory-like progenitor, effector and terminally exhausted cells that exhibit differing functional and self-renewal capacities. However, the cellular and molecular processes involved in the differentiation of these subsets within melanoma is not well understood. Exploring the intricacies of CD8 T cell differentiation towards an effector profile can identify novel immunotherapeutic targets. Thus, the long-term goal of this project is to elucidate the mechanisms regulating effector CD8 T cell differentiation and function in melanoma. CD4 T cell production of cytokines provide help to CD8 T cells. Recent studies have uncovered the cytokine IL- 21 as a critical signal produced by CD4 T cells to help promote CD8 T cell maintenance in chronic infection. However, the direct effects of IL-21 produced by CD4 T cells on CD8 T cell differentiation and function in cancer remains unknown. Preliminary data presented in this proposal suggest that IL-21 producing CD4 T cells induce an effective antitumor response dependent on CD8 T cells. Additionally, it has been previously found that IL-21 signaling induces the transcription factor BATF, which is known to cooperatively bind with IRF4 to induce changes in the chromatin landscape. This has led to the hypothesis that the IL-21-BATF pathway enhances melanoma-infiltrating effector CX3CR1+ CD8 T cells and their function via BATF-IRF4 mediated transcriptional regulation. Aim 1 will determine if adoptively transferred IL-21-producing CD4 T cells enhance effector CX3CR1+ CD8 T cell differentiation. The effect of CD4 T cell-derived IL-21 on CD8 T cell differentiation and function will be determined in vivo. Then, it will be determined if IL-21R signaling is intrinsically necessary for the CD8 T cell response to IL-21 producing CD4 T cell help. Aim 2 will investigate the mechanism of BATF-mediated tumor-infiltrating CD8 T cell differentiation. These experiments will determine if BATF-IRF4 interaction is necessary to promote tumor-infiltrating CX3CR1+ CD8 T cells. Furthermore, changes in BATF-mediated chromatin accessibility in CD8 T cell differentiation and function will be assessed. This proposal will help in understanding how CD8 T cells differentiate and function in melanoma. This is in line with the mission of NCI, as the results of this project could lead to the identification of BATF as a novel therapeutic mechanism to enhance effector CD8 T cell differentiation to fight cancer.