Batf3+ dendritic cells, CD8+ T cells and related chemokines in the melanoma tumor microenvironment: association with immunotherapy efficacy

肿瘤微环境的组成影响黑色素瘤患者对免疫治疗的反应。肿瘤微环境中CD8+ T细胞的存在丰富了抗pd -1应答者，但这是一个不完美的预测性生物标志物。最近的临床前工作表明，肿瘤微环境中表达亮氨酸拉链转录因子atf -样3 （Batf3+ DCs）的树突状细胞的存在也对免疫治疗效果起着至关重要的作用。先前的研究表明，Batf3+ dc负责将CD8+ T细胞募集到小鼠的肿瘤微环境中。本提案旨在用黑色素瘤患者的人体组织样本证实这一假设，从而确定免疫治疗黑色素瘤疗效的新生物标志物。作为这项工作的一个组成部分，我们将确定趋化因子的细胞来源，以了解导致CD8+ T细胞和Batf3+ dc向肿瘤微环境募集的机制。临床前实验表明，CXCL9和CXCL10对活化的CD8+ T细胞的募集很重要，而CCL4或XCL1对Batf3+ dc的募集很重要。更详细地了解哪些趋化因子与人类黑色素瘤中Batf3+ dc和CD8+ T细胞的募集相关，可以开辟基于改善免疫细胞募集的治疗策略。非炎症性肿瘤微环境最终可以通过靶向趋化因子的传递或诱导转变为炎症性肿瘤微环境。这可能会导致未来的免疫治疗策略，以解决目前对抗pd -1无反应的患者。

The composition of the tumor microenvironment influences the response of melanoma patients to immunotherapy. The presence of CD8+ T cells within the tumor microenvironment enriches for responders to anti-PD-1, yet this is an imperfect predictive biomarker. Recent preclinical work has suggested that the presence of dendritic cells expressing the basic leucine zipper transcription factor ATF-like 3 (Batf3+ DCs) within the tumor microenvironment also plays a crucial role for immunotherapy efficacy. Previous investigations have indicated that Batf3+ DCs are responsible for the recruitment of CD8+ T cells to the tumor microenvironment in mice. The present proposal is designed to confirm this hypothesis with human tissue samples of melanoma patients and thereby identify novel biomarkers for efficacy of immunotherapy in melanoma. As a component of this work, we will identify the cellular sources of chemokines to understand the mechanisms leading to the recruitment of CD8+ T cells and Batf3+ DCs to the tumor microenvironment. Preclinical experiments have suggested that CXCL9 and CXCL10 are important for the recruitment of activated CD8+ T cells, and either CCL4 or XCL1 for the recruitment of Batf3+ DCs. A more detailed understanding of which chemokines are of relevance for recruitment of Batf3+ DCs and CD8+ T cells in human melanoma could open a therapeutic strategy based on improving immune cell recruitment. A non-inflamed tumor microenvironment could eventually be turned into an inflamed tumor microenvironment by targeted chemokine delivery or induction. This might lead to a future immunotherapeutic strategy to address patients that currently do not respond to anti-PD-1.