Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+T cell activity

作者全名："Luan, Xiaojin; Lei, Ting; Fang, Jie; Liu, Xue; Fu, Huijia; Li, Yiran; Chu, Wei; Jiang, Peng; Tong, Chao; Qi, Hongbo; Fu, Yong"

作者地址："[Luan, Xiaojin; Lei, Ting; Liu, Xue; Li, Yiran; Chu, Wei; Tong, Chao; Qi, Hongbo; Fu, Yong] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Maternal & Fetal Med, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Luan, Xiaojin; Lei, Ting; Li, Yiran; Chu, Wei; Tong, Chao; Fu, Yong] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, Chongqing 400016, Peoples R China; [Qi, Hongbo] Chongqing Med Univ, Women & Childrens Hosp, Chongqing 401147, Peoples R China; [Fang, Jie] Jiangsu Univ, Affiliated Hosp, Dept Gynecol, Zhenjiang 212001, Jiangsu, Peoples R China; [Liu, Xue] Chongqing Med Univ, Yongchuan Hosp, Dept Obstet, Chongqing 402160, Peoples R China; [Fu, Huijia] Chongqing Med Univ, Affiliated Hosp 1, Dept Reprod Med Ctr, Chongqing 400016, Peoples R China; [Jiang, Peng] Chongqing Med Univ, Affiliated Hosp 1, Dept Gynecol, Chongqing 400016, Peoples R China"

通信作者："Tong, C; Qi, HB; Fu, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Maternal & Fetal Med, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Qi, HB (通讯作者)，Chongqing Med Univ, Women & Childrens Hosp, Chongqing 401147, Peoples R China."

来源：MOLECULAR THERAPY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001193833500001

JCR分区：Q1

影响因子：12.1

年份：2024

卷号：32

期号：2

开始页：469

结束页：489

文献类型：Article

关键词：　

摘要："Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor -associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C -X -C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications."

基金机构："National Key Research and Development Program of China [2022YFC2704702]; General Program of National Natural Science Foundation of China [82271714, 82171662]; National Natural Science Foundation of China [U21A20346]"

基金资助正文："This study was supported by the National Key Research and Development Program of China (2022YFC2704702) , General Program of National Natural Science Foundation of China (no. 82271714, to Y.F.) , General Program of National Natural Science Foundation of China (no. 82171662, to H.Q.) , and Joint Funds of the National Natural Science Foundation of China (no. U21A20346, to H.Q.) ."