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

黑色素瘤肿瘤微环境中的 Batf3 树突状细胞、CD8 T 细胞和相关趋化因子：与免疫治疗疗效的关联

基本信息

批准号：
439686648
负责人：
Dr. Robin Reschke
金额：
--
依托单位：
Klinik und Poliklinik für Dermatologie und Venerologie
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2020
资助国家：
德国
起止时间：
2019-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/439686648?language=en
关键词：
Batf3+dendritic cells CD8+related

项目摘要

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.

肿瘤微环境的组成影响黑色素瘤患者对免疫疗法的反应。肿瘤微环境中CD 8 + T细胞的存在丰富了抗PD-1的应答者，但这是一个不完美的预测生物标志物。最近的临床前研究表明，肿瘤微环境中表达碱性亮氨酸拉链转录因子ATF样3（Batf 3 + DCs）的树突状细胞的存在也对免疫治疗的疗效起着至关重要的作用。以前的研究表明，Batf 3 + DC负责将CD 8 + T细胞募集到小鼠肿瘤微环境中。本提案旨在用黑色素瘤患者的人组织样品证实这一假设，从而鉴定用于黑色素瘤免疫治疗功效的新生物标志物。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CD 8 + T细胞和Batf 3 + DC募集到肿瘤微环境的机制。临床前实验表明，CXCL 9和CXCL 10对于激活的CD 8 + T细胞的募集是重要的，CCL 4或XCL 1对于Batf 3 + DC的募集是重要的。更详细地了解哪些趋化因子与人类黑色素瘤中Batf 3 + DC和CD 8 + T细胞的募集相关，可以打开基于改善免疫细胞募集的治疗策略。通过靶向趋化因子递送或诱导，非炎症肿瘤微环境最终可以转变为炎症肿瘤微环境。这可能会导致未来的免疫治疗策略，以解决目前对抗PD-1没有反应的患者。