Cao, Chen, and Li et al. found that the anticancer effect of several mAb therapies (cetuximab, trastuzumab, and rituximab, targeting EGFR, HER2, and CD20, respectively) was enhanced in the presence of macrophages. From a broad screening, the drug paclitaxel was identified to increase macrophage phagocytic ability, promote an M1 phenotype with NFκB activation, and downregulate the cell surface marker CSF1R; selective CSF1R knockdown also increased macrophage phagocytosis. In target-expressing mouse and PDX tumor models, combination paclitaxel and targeted therapy improved antitumor efficacy over either monotherapy.
Contributed by Alex Najibi
ABSTRACT: Macrophages are essential in eliciting antibody-dependent cellular phagocytosis (ADCP) of cancer cells. However, a satisfactory anticancer efficacy of ADCP is contingent on early antibody administration, and resistance develops along with cancer progression. Here, we investigate the mechanisms underlying ADCP and demonstrate an effective combinatorial strategy to potentiate its efficacy. We identified paclitaxel as a universal adjuvant that efficiently potentiated ADCP by a variety of anticancer antibodies in multiple cancers. Rather than eliciting cytotoxicity on cancer cells, paclitaxel polarized macrophages toward a state with enhanced phagocytic ability. Paclitaxel-treated macrophages down-regulated cell surface CSF1R whose expression was negatively correlated with patient survival in multiple malignancies. The suppression of CSF1R in macrophages enhanced ADCP of cancer cells, suggesting a role of CSF1R in regulating macrophage phagocytic ability. Together, these findings define a potent strategy for using conventional anticancer drugs to stimulate macrophage phagocytosis and promote the therapeutic efficacy of clinical anticancer antibodies.
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (2) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Dua
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (2) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (3) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (4) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (5) Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (6) Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (7) Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA. (8) Department of Surgery, City of Hope, Duarte, CA 91010, USA. (9) Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. (10) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA 91010, USA. (11) Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA. (12) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
