Carcinoembryonic antigen-related cell adhesion moclecule-1 regulates myeloid-cell-dependent tumor angiogenesis by inhibition of G-CSFR-Bv8 pathway (66.19)

Abstract

Abstract Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) promote tumor angiogenesis and are refractory to VEGF antibodies treatment. Bv8 expressed in MDSCs has recently been shown to modulate MDSCs mobilization and tumor angiogenesis. Carcinoembryonic antigen-related cell adhesion moclecule-1(CEACAM1) is highly expressed on Gr1+ myeloid cells, however the role of CEACAM1 in myeloid cells mediated tumor angiogenesis has not been investigated. We have demonstrated that tumor growth and angiogenesis was significantly enhanced in Ceacam1-/- mice, which was independent on T and B cells . Meanwhile MDSCs infiltration in tumor, spleen and blood was increased. Tumors coinjected with MDSCs from Ceacam1-/- mice exhibited increased angiogenesis compared to coinjection with MDSCs from control mice. Depletion of Gr1+ cells inhibited tumor growth and angiogenesis in control and Ceacam1-/- mice. MDSCs from Ceacam1-/- mice expressed higher Bv8 in vitro and in vivo. Further we have shown that CEACAM1 recruited Src-homology-phosphatase-1 (SHP-1) to attenuate granulocyte colony-stimulating factor receptor (G-CSFR)-Bv8 pathway. Reconsititution of CEACAM1 into Ceacam1-/- bone marrow cells restored tumor growth and angiogenesis to normal level, and mutations of immunoreceptor tyrosine-based inhibitory motifs ITIMs abolished this restoration. Therefore, we identified CEACAM1, as an inhibitory regulator of G-CSFR-Bv8 pathway, negatively regulates myeloid-cell-dependent tumor angiogenesis.