RIAM regulates myeloid cell fate commitment and macrophage polarization and controls tumor progression

Abstract

Abstract Initiation of immune responses requires integrin-mediated adhesion between T cells and APC, linking innate and adaptive immunity. Integrins also regulate leukocyte trafficking and extravagation at sites of inflammation. Among the few molecules implicated in integrin activation is the Rap1-interacting molecule (RIAM). Tumor-driven emergency myelopoiesis induces expansion of myeloid progenitors and output of immature, immunosuppressive myeloid derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). TAMs are classified into two groups: M1, which have a pro-inflammatory and anti-tumor function and M2, which have an anti-inflammatory role and facilitate tumor progression. To determine whether RIAM affects the properties of myeloid cells and tumor progression, we generated mice with conditional targeting of RIAM and crossed them with LysMCre mice (RIAMfl/flLysMCre) to delete RIAM specifically in the myeloid compartment. Using the B16-F10 melanoma and MC17-51 fibrosarcoma tumor models, we determined that RIAMfl/flLysMCre mice displayed an accelerated growth and significantly larger tumors compared to RIAMfl/fcontrol mice. There were no numerical differences in CD11b+F4/80+ macrophages, CD11b+Ly6ChiLy6G− monocytic (M-MDSC), CD11b+Ly6CloLy6G+ polymorphonuclear (PMN-MDSC) or CD11c+MHCII+ dendritic cells between the two groups. However, TAMs and splenic macrophages of RIAMfl/flLysMCre mice exhibited an M2-like phenotype. Bone marrow derived macrophages from RIAMfl/flLysMCre had an imprinted M2 polarization program. Thus, RIAM has a previously unidentified role in myeloid cell fate commitment that regulates macrophage polarization and controls tumor progression.