T cell–induced CSF1 promotes melanoma resistance to PD1 blockade
2018
Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of
tumor-associated macrophages(TAMs). We show that CSF1 is expressed in human
melanoma, and patients with metastatic
melanomahave increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of
CD8+ T cells and
CD163+ TAMs. Human
melanomacell lines consistently produced CSF1 after exposure to
melanoma-specific
CD8+ T cells or T cell–derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated
CD8+ T cells. Mining of publicly available transcriptomic data sets suggested co-enrichment of
CD8+ T cells with CSF1 or various TAM-specific markers in human
melanoma, which was associated with nonresponsiveness to programmed cell death protein 1 (PD1) checkpoint blockade in a smaller patient cohort. Combination of anti-PD1 and anti–CSF1 receptor (CSF1R) antibodies induced the regression of BRAF
V600E-driven, transplant mouse
melanomas, a result that was dependent on the effective elimination of TAMs. Collectively, these data implicate CSF1 induction as a
CD8+ T cell–dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in
melanomasrefractory to
immune checkpointblockade and, possibly, other T cell–based therapies.
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