Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppres- sing myeloid-derived suppressor cells (MDSC) andM2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphati- dylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvi- ronment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2- to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity.