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-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphatidylserine-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 microenvironment 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.
Authors' Affiliation: Department of Pharmacology and Simmons and Hamon Cancer Centers, University of Texas Southwestern Medical Center, Dallas, Texas.
Yi
Y
Yin
Xianming
X
Huang
Kristi D
KD
Lynn
Philip E
PE
Thorpe
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D000077143:Docetaxel; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010718:Phosphatidylserines / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D043823:Taxoids / Q000627:therapeutic use; D059016:Tumor Microenvironment
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D016207:Cytokines; D010718:Phosphatidylserines; D043823:Taxoids; D000077143:Docetaxel; C547825:bavituximab