Abstract B2: Coexpression of effector T cell-associated chemokine receptors defines T-cell subsets with different roles in antitumor response and toxicity of dual checkpoint blockade

Abstract

Abstract Dual checkpoint blockade has yielded impressive clinical responses in cancer treatment, but only a subset of patients responds and immune-related adverse events (irAE) are common, frequently leading to treatment discontinuation. Both CCR5 and CXCR3 expression are associated with effector T-cell trafficking and favorable outcomes in various tumors, but only CXCR3 was shown to exhibit a nonredundant role for cytotoxic T-cell trafficking across tumor vessels, while CCR5 has been implicated in recruitment of regulatory T cells to the tumor microenvironment. Here, we explored the coexpression of T cell-associated chemokine receptors in human melanoma and studied the effect of genetic and pharmacologic manipulation of CCR5 on PD-1/CTLA-4 (P1C4) blockade efficacy and toxicity observed in B16 tumor-bearing mice. We found that in human melanoma CCR5 and CXCR3 expression characterizes different T-cell subsets based on their coexpression with other chemokine receptors at the single-cell level. These subsets exhibit distinct phenotypic and functional characteristics in blood and tumor; CXCR3 indicated less differentiated T cells with greater proliferative potential while CCR5 expression was more abundant on terminal effector cells. In addition, subsets expressing only CXCR3 were increased in patients who received checkpoint blockade while subsets that express CCR5 were unaffected by the treatment. In murine melanoma, dual checkpoint inhibition using PD-1/CTLA-4 blockade significantly increased CXCR3, but not CCR5 expression on T cells. Moreover, a murine model of PD-1/CTLA-4 blockade-induced irAE showed high levels of CCR5+ T cells in toxicity target organs. When PD-1/CTLA-4 inhibitors were administered to either CCR5-KO mice or WT mice treated with the CCR5 antagonist maraviroc, there was a significant decrease in tumor growth and improved survival compared to WT mice receiving P1C4 alone. Together these results reveal distinct, potentially opposite roles for CCR5 and CXCR3 subsets specifically in the setting of dual checkpoint blockade, that can be redirected to improve efficacy and reduce toxicity observed in melanoma. Citation Format: Rodney J.M. Macedo Gonzales, David Harle, Ximi K. Wang, Alexandra Matschiner, Ran Reshef. Coexpression of effector T cell-associated chemokine receptors defines T-cell subsets with different roles in antitumor response and toxicity of dual checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B2.