PSGL-1 is a phagocytosis checkpoint that enables tumor escape from macrophage clearance
Cheng Zhong, Lixiang Wang, Yujia Liu, Xinyu Wang, Zijin Xia, Yiyi Li, Yao Zhang, Jing Liao, Xianmiao Wang, Chen-Yang Liao, Chunliu Huang, Xiumei Wang, Chengzhou Mao, Yongyi Feng, Congzhou Luo, W.F. Mai, Hongrui Song, Yue Sheng, Yingyi He, Xiaolei Wei, Hui Zhang, Hong Yuan, Yi Wei, Jun Chen
Abstract
Cancer immunotherapies exhibit impressive efficacy in some cancers but show only limited benefits for refractory hematological malignancies. The complex immune escape mechanisms of hematological cancers remain unclear. Here, we found that P-selectin glycoprotein ligand 1 (PSGL-1) was highly expressed by hematological cancers and negatively correlated with cancer prognosis. PSGL-1 deficiency in tumors suppressed the progression of multiple mouse models of hematological cancer by promoting infiltration of macrophages and their phagocytic activity. Tumor PSGL-1 inhibited the interaction between tumor ICAM-1 and CD11a/CD18 integrin (LFA-1) in macrophages, thereby suppressing prophagocytic signaling downstream of LFA-1. A humanized antibody targeting human PSGL-1 (αhPSGL-1) efficiently triggered macrophage phagocytosis of human hematological malignancies in vitro and slowed cancer progression in vivo. Additionally, PSGL-1 blockade potentiated the efficacy of doxorubicin chemotherapy and anti-CD47 and anti-CD38 antibody therapy. Therefore, PSGL-1 is a previously undescribed phagocytosis checkpoint, and targeting PSGL-1 could be a promising immunotherapy strategy for treating hematological malignancies.