Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy

Abstract

Despite compelling rates of durable clinical responses to PD-1 blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8 + T cell response in tumor-bearing mice treated with anti-PD-1, but were not required for the infiltration of CD8 + T cells into tumors. The anti-PD-1- induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103 + dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands within murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non- responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes. Chow et al. find the CXCR3 chemokine system is not required for CD8 + T cell migration into the tumor, but rather for the enhancement of the intratumoral CD8 + T cell response in the context of PD-1 blockade. The CXCR3 chemokine system may serve as a biomarker for sensitivity to PD- 1 blockade and a target for improving clinical outcomes.