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

Abstract

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.

Scavenger Receptors: Novel Roles in the Pathogenesis of Liver Inflammation and Cancer

“…Interestingly, early results in patients where biopsies were undertaken did show a reduction of antiinflammatory intratumoral stabilin-1 þ macrophages and an increase in proinflammatory/adaptive immune cell subsets in selected patients. 176 This trial is ongoing and overall therapeutic efficacy is awaited, yet the data are consistent with the detrimental effects of TAM scavenger receptors and their role in driving an immunosuppressive TME, and also highlight therapeutic potential for their targeting within the context of HCC.…”

“…The first of these targeted scavenger receptor SCARB-1 in HCV cell entry in the context of liver transplantation 127 and the second is an early-phase clinical trial currently underway, targeting the scavenger receptor stabilin-1 on TAMs in solid tumors, including HCC. 176 In addition, scavenger receptors have also been explored as biomarkers of disease states, and here we highlight their potential as biomarkers in different etiologies of liver disease (►Fig. 2).…”

Macrophage scavenger receptors: Tumor support and tumor inhibition

“…Stabilin-1 performs endocytosis, phagocytosis, intracellular sorting of newly synthetized proteins and transcytosis of growth hormone family member placental lactogen (9,(139)(140)(141)(142)(143)(144). Large body of evidence demonstrated that stabilin-1/CLEVER-1 can mediate cell-matrix and cell-cell interactions during primary tumor growth and in metastatic state (135,138,(145)(146)(147).…”

Deficiency for scavenger receptors Stabilin‐1 and Stabilin‐2 leads to age‐dependent renal and hepatic depositions of fasciclin domain proteins TGFBI and Periostin in mice

“…As TGFBI and POSTN constitute paralogs it seems probable that both proteins contribute in certain diseases (Schwanekamp et al, 2016). Stab1 and Stab2 single inhibition mediates beneficial effects in atherosclerosis development (Manta et al, 2022), anti-Stab1 inhibition is in clinical trials in immuneoncology (Virtakoivu et al, 2021). We here assess the possible side effects of single and double Stabilin deficiency or inhibition on the scavenging of POSTN and TGFBI from the circulation and their tissue distribution.…”

“…Previously, we showed that Stab1/Stab2-double-knockout mice (Stab-DKO) present an impaired kidney function and a decreased lifespan likely due to their impaired scavenging function through LSECs (Schledzewski et al, 2011). Only recently, we were able to show that single Stabilin inhibition reduces atherosclerosis development (Manta et al, 2022), furthermore, anti-Stab1 antibodies are in initial clinical trials as an immunomodulatory cancer treatment (Virtakoivu et al, 2021).…”