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目标，由于其生存率低， 最近的治疗进展。目前的策略集中在CD 8 T细胞上，这些细胞在体内进入功能障碍状态。 肿瘤微环境最近的研究发现，肿瘤内的CD 8 T细胞由一种免疫调节剂组成。 记忆样祖细胞、效应细胞和终末耗竭细胞的异质群体， 不同的功能和自我更新能力。然而，参与细胞和分子过程， 黑色素瘤中这些亚群的分化还不清楚。探索CD 8 T细胞的复杂性 向效应物谱的分化可以鉴定新的免疫学靶标。因此，长期 本项目的目的是阐明调节效应CD 8 T细胞分化的机制， 在黑色素瘤中的作用 CD 4 T细胞产生的细胞因子为CD 8 T细胞提供帮助。最近的研究发现细胞因子IL- 21作为由CD 4 T细胞产生的关键信号，以帮助促进慢性感染中的CD 8 T细胞维持。 然而，由CD 4 T细胞产生的IL-21对CD 8 T细胞分化和功能的直接作用在CD 4 T细胞中并不明显。 癌症仍然未知。该提案中提出的初步数据表明，产生IL-21的CD 4 T细胞 诱导依赖于CD 8 T细胞有效抗肿瘤应答。此外，之前还发现 IL-21信号传导诱导转录因子BATF，已知其与IRF 4协同结合， 引起染色质景观的变化。这导致了IL-21-BATF途径 通过BATF-IRF 4增强黑色素瘤浸润效应CX 3CR 1 + CD 8 T细胞及其功能 介导的转录调控。 目的1将确定过继转移的产生IL-21的CD 4 T细胞是否增强效应CX 3CR 1 + CD 8 T细胞分化。CD 4 T细胞来源的IL-21对CD 8 T细胞分化和功能的影响将被证实。 在体内测定。然后，将确定IL-21 R信号传导对于CD 8 T细胞是否是内在必需的。 产生IL-21的CD 4 T细胞的帮助。 目的2探讨BATF介导肿瘤浸润性CD 8 T细胞分化的机制。 这些实验将确定BATF-IRF 4相互作用是否是促进肿瘤浸润性CX 3CR 1 + CD 8 T细胞。此外，BATF介导的染色质可及性在CD 8 T细胞分化和 功能将被评估。 这一提议将有助于理解CD 8 T细胞如何在黑色素瘤中分化和发挥作用。这是符合 与NCI的使命，因为这个项目的结果可能导致BATF作为一种新的识别 增强效应CD 8 T细胞分化以对抗癌症的治疗机制。

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.