Journal Article Epublish 1 citation
PubMed: 39664577 DOI: 10.7150/ijbs.100607
Complement C1q is a key player in tumor-associated macrophage-mediated CD8 T cell and NK cell dysfunction in malignant pleural effusion.
Int J Biol Sci 20(15):5979-5998
Authors: Feng-Shuang Yi, Xin Qiao, Shu-Feng Dong, Qing-Yu Chen, Rui-Qi Wei, Ming-Ming Shao, Huan-Zhong Shi
Affiliations
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China. Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin University, Tianjin 300222, China.
Abstract
Macrophages play a crucial role in malignant pleural effusion (MPE), a frequent complication of advanced cancer. While C1q macrophages have been identified as a pro-tumoral cluster, direct evidence supporting the role of C1q-mediated macrophages remains to be elucidated. This study employed global and macrophage-specific knockout mice to investigate the role of C1q in MPE. The data demonstrated that C1q deficiency in macrophages suppressed MPE and prolonged mouse survival. scRNA-seq analysis of the C1qa mouse MPE model revealed that C1q deficiency significantly decreased the proportion of M2 macrophages in MPE. experiments suggested that C1q expression was gradually upregulated during M2 polarization, which was C1q-dependent, as was antigen presentation. Deficiency of C1q in macrophages rescued the exhausted status of CD8 T cells and enhanced the immune activity of CD8 T cells and NK cells in both MPE and pleural tumors. Cell-to-cell interaction analysis demonstrated that C1q deficiency attenuated the immunoinhibitory effects of macrophages on NK cells by downregulating the CCR2-CCL2 signaling axis. Metabolomic analysis revealed significantly elevated hippuric acid levels in C1q-deficient mouse MPE. Treatment with either hippuric acid or a CCR2 antagonist inhibited MPE and tumor growth, with an even more pronounced effect observed when both treatments were combined.
MeSH
Cells, Pleural Effusion, Biological Science Disciplines, Killer Cells, Natural, Macrophages, Neoplasms, Cell Communication, Metabolomics, Complement System Proteins, Therapeutics, T-Lymphocytes, Complement C1Q, Tumor-Associated Macrophages, Pleural Effusion, Malignant