PHST001与标准治疗化疗联合可增强巨噬细胞介导的肿瘤细胞清除

Chemotherapy exposure induces cellular stress and can upregulate ‘Eat me' signals on the surface of cancer cells thereby targeting these cells for clearance by macrophage phagocytosis. However, this phagocytosis can be inhibited by ‘Don't eat me' (DEM) signals like CD24 on the surface of tumor cells. The clinical-stage anti-CD24 monoclonal antibody PHST001 blocks the CD24 DEM signal and promotes macrophage phagocytosis of target cells, raising the possibility that cotreatment with PHST001 and chemotherapy could provide combinatorial benefit to patients. To identify potential PHST001 and chemotherapy combinations, we screened 17 standard-of-care chemotherapy agents with PHST001 in coculture of peripheral monocyte-derived human macrophages and each of 13 cell lines representing 6 different cancer indications. We identified several common classes of chemotherapy drugs, including taxanes, platins, topoisomerase inhibitors, and anti-metabolites that enhance PHST001-induced macrophage clearance of cancer cells. We found that while cancer cells are generally sensitive to chemotherapy, macrophages display remarkable resistance to many chemotherapy agents. We further validated PHST001 combination with several chemotherapies in two-way dose-response experiments and identified chemotherapies that synergize with PHST001 to clear cancer cells in macrophage coculture. We subsequently validated select chemotherapy and PHST001 combinations (e.g. cisplatin) in vivo with mouse xenograft studies. Mechanistically, we discovered that certain chemotherapy agents increased the surface expression of the ‘Eat me' signal phosphatidylserine (PS) on cancer cells, while others directly enhanced the phagocytosis capacity of macrophages. Taken together, these data support therapeutic combination of PHST001 with multiple standard-of-care chemotherapies to deepen tumor-killing response in patients.