Clever-1/Stabilin-1 Controls Cancer Growth and Metastasis

Abstract

Purpose: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.Experimental Design: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.Results: Clever-1-deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.Conclusion: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. Clin Cancer Res; 20(24); 6452-64. Ó2014 AACR.

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

“…To test this hypothesis in vivo, we used Tie-2 Cre and Lys2 Cre strains to generate cell-selective knockouts. We have previously confirmed their selectivity and efficiency in knocking down stabilin-1 (26). We have shown that in our Tie-2 Cre model, stabilin-1 is absent from endothelium (ENDO stab-1 −/− ) but macrophage expression is maintained.…”

“…Stabilin-1 knockout mice and cell-specific mice were generated as previously described (26). CAG-Dsred*MST 1Nagy/J (stock 005441) were from The Jackson Laboratory.…”

Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes

“…In macrophages, stabilin-1 is known to be a good marker for immunosuppressive M2 cells both in vitro and in vivo (13,16,18,19,(31)(32)(33)(34) (19,32). Notably, however, no link between stabilin-1 and the immunosuppressive mechanisms of M2 macrophages has been found earlier.…”

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

“…Selective extravasation of different leukocyte subsets may also be mediated by additional molecules including common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) (135) and Fas ligand (FasL) (136). CLEVER-1, also known as stabilin-1 and FEEL-1, is a multifunctional scavenging receptor expressed constitutively on lymphatic endothelial cells (LECs) and type 2 macrophages and induced by inflammation on blood endothelial cells (137, 138).…”

“…In a mouse model of melanoma, levels of CLEVER-1 correlated with increased infiltration by FoxP3 + T regs and type II macrophages. Following administration of anti-CLEVER-1 antibody, numbers of T regs and type II macrophages were reduced, and there was increased immune activation and decreased tumor growth (135). FasL mediates T cell apoptosis and can be induced on blood vascular endothelial cells in solid tumors by tumor-derived VEGF-A, prostaglandin E2, and IL-10 (136).…”