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

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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.