PSGL-1 is a phagocytosis checkpoint that enables tumor escape from macrophage clearance

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-06-13 DOI:10.1126/sciimmunol.adn4302

Cheng Zhong, Lixiang Wang, Yujia Liu, Xinyu Wang, Zijin Xia, Yiyi Li, Yao Zhang, Jing Liao, Xianmiao Wang, Chenyang Liao, Chunliu Huang, Xiumei Wang, Chengzhou Mao, Yongyi Feng, Congzhou Luo, Wenhao Mai, Hongrui Song, Yue Sheng, Yingyi He, Xiaolei Wei, Hui Zhang, Hong Yuan, Wei Yi, Jun Chen

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引用次数: 0

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.

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PSGL-1是一种吞噬检查点，可使肿瘤逃避巨噬细胞的清除

癌症免疫疗法在某些癌症中表现出令人印象深刻的疗效，但对难治性血液系统恶性肿瘤的疗效有限。血液学癌症复杂的免疫逃逸机制尚不清楚。本研究发现p -选择素糖蛋白配体1 （PSGL-1）在血液病中高表达，与癌症预后呈负相关。肿瘤中PSGL-1缺失通过促进巨噬细胞的浸润及其吞噬活性，抑制多种小鼠血液癌模型的进展。肿瘤PSGL-1抑制肿瘤ICAM-1与巨噬细胞中CD11a/CD18整合素（LFA-1）的相互作用，从而抑制LFA-1下游的前吞噬细胞信号传导。一种靶向人PSGL-1的人源化抗体（αhPSGL-1）在体外有效地触发了人血液恶性肿瘤的巨噬细胞吞噬，并在体内减缓了肿瘤的进展。此外，PSGL-1阻断增强了阿霉素化疗和抗cd47和抗cd38抗体治疗的疗效。因此，PSGL-1是一个先前未被描述的吞噬检查点，靶向PSGL-1可能是治疗血液系统恶性肿瘤的一种有前途的免疫治疗策略。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.