Mannose receptor regulates macrophage polarization in the tumor microenvironment (66.31)

Abstract

Abstract Tumor-associated macrophages (TAMs) share properties with M2 macrophages (MΦ),including high IL10 and mannose receptor (MR) expression. MR cross-linking differentiates DCs into APCs inducing T-cell anergy. However,although MR is abundantly expressed on M2 MΦ,its role on TAMs remains poorly understood. To address this question,we isolated 3 novel recombinant antibodies(scFv) against the human mannose binding domain of MR (CRD4-MR),and set up transwell cocultures allowing chemical exchanges between MΦ and ovarian cancer cells. MΦ phenotype was assessed by FACS,qPCR and bead-based FACS. We also challenged wild type,MR+/- and MR-/- mice with ovarian cancer. We first confirmed that MΦ coculture with tumor cells triggers a tumor associated phenotype and showed that 1 anti-CRD4-MR scFv could block the phenotype switch. We further demonstrated that tumor-released mesothelin (MSLN), but not GPI-anchor truncated MSLN,bound to MR-expressing MΦ,and that MSLN binding could be blocked by all 3 anti-CRD4-MR scFvs. Finally, although tumor challenged MR-/- mice did not survive significantly longer than the wild type,MR+/- mice exhibited lower tumor burden and prolonged survival. MR+/- ascites MΦ secreted significantly higher levels of TNF-a consistent with a pro-inflammatory phenotype. Altogether,tumor-released mesothelin binds to MR and blocking of CRD4-MR binding inhibits TAM phenotype and promotes MΦ with proinflammatory proprieties. Blocking MR function could have therapeutic potential.