Systemic blockade of Clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors

Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell targeting therapies. Thus, agents that can reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Here, we report that immunotherapeutic targeting of the macrophage scavenger receptor Clever-1 in heavily pretreated metastatic cancer patients was able to induce a significant increase and activation of peripheral T-cells. Anti-Clever-1 (FP-1305) administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. Mechanistically, Clever-1 inhibition impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved macrophage cross-presentation of scavenged antigens. Our results reveal a non-redundant role played by the receptor Clever-1 in suppressing adaptive immune cell activation in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch potentially leading to intratumoral proinflammatory responses in metastatic cancer patients.