Rodney Macedo

"Co-expression of chemokine receptors define T-cell subsets with mixed roles in antitumor response and toxicity of checkpoint blockade"

Dual checkpoint blockade has yielded impressive clinical responses in cancer treatment, but only a subset of patients responds, and immune-related adverse events (irAEs) are common, leading to discontinuation. Both, CCR5 and CXCR3 expression are associated with T cell trafficking and favorable outcomes in various tumors, but only CXCR3 was shown to exhibit a non-redundant role for cytotoxic T cell trafficking. Here, we explored the co-expression of T-cell associated chemokine receptors in human melanoma and studied the effect of genetic inhibition of CCR5 or CXCR6 on PD-1/CTLA-4 blockade efficacy and toxicity profile observed in B16 tumor-bearing mice. We found that in human melanoma the co-expression of CCR5, CXCR3 and CXCR6 define different subsets with distinct phenotypic and functional characteristics; CXCR3 indicates less differentiated T-cells with greater proliferative potential while CCR5/CXCR6 subsets are more frequent on effector and exhausted cells. In patients that received checkpoint blockade we observed an increase of CXCR3 subsets. In murine melanoma, PD-1/CTLA-4 blockade significantly increases CXCR6/CXCR3 subsets in the tumor, while increasing CXCR6/CCR5 subsets in target organs of irAEs. When dual checkpoint blockade was administered to either CCR5KO mice, there was a significant decrease in tumor growth, improved survival and reduced liver-infiltration of T and NK cells when compared to CXCR6KO or WT mice receiving checkpoint alone. Together these results reveal distinct, potentially opposite roles for CCR5, CXCR6 and CXCR3 subsets in the setting of checkpoint blockade that can be redirected to improve efficacy and reduce toxicity observed in melanoma.