The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2⁺ PMN-MDSCs, enhanced the activation of CD8⁺ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2⁺ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2⁺ PMN-MDSCs, boosted CD8⁺ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2⁺ PMN-MDSCs as a mechanism of immunosuppression.