PD-1 and CTLA-4 Serve As Major Gatekeepers for Effector and Cytotoxic T-cell Potentiation by Limiting a CXCL9/10-CXCR3-IFNγ Positive Feedback Loop

CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy. Results from a panel of and ex vivo 3D tumor models imply that, beyond driving CD8+ T cells into T-cell exhaustion, a major role of PD-1 and CTLA-4 is in limiting the CXCR3-based self-feeding mechanism of T cell potentiation. This may explain why patients that are CXCL9/CXCL10 tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10. It also suggests a therapeutic role for CXCL9-Fc or CXCL10-Fc therapy; herein we demonstrate significant anti-tumor activity in multiple murine tumor models with such agents.