Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma
Year: 2025
Type: preprint
Abstract: Tumor-associated macrophages are a key component that contributes to the immunosuppressive microenvironment in human cancers. However, therapeutic targeting of macrophages has been a challenge in clinic due to the limited understanding of their heterogeneous subpopulations and distinct functions. Here, we identify a unique and clinically relevant CD19$^+$ subpopulation of macrophages that is enriched in many types of cancer, particularly in hepatocellular carcinoma (HCC). The CD19$^+$ macrophages exhibit increased levels of PD-L1 and CD73, enhanced mitochondrial oxidation, and compromised phagocytosis, indicating their immunosuppressive functions. Targeting CD19$^+$ macrophages with anti-CD19 chimeric antigen receptor T (CAR-T) cells inhibited HCC tumor growth. We identify PAX5 as a primary driver of up-regulated mitochondrial biogenesis in CD19$^+$ macrophages, which depletes cytoplasmic Ca$^{2+}$, leading to lysosomal deficiency and consequent accumulation of CD73 and PD-L1. Inhibiting CD73 or mitochondrial oxidation enhanced the efficacy of immune checkpoint blockade therapy in treating HCC, suggesting great promise for CD19$^+$ macrophage-targeting therapeutics.
Source: arXiv (Cornell University)
Authors: Wang, Junli, Cao, Wanyue, Huang, Jinyan, Zhou, Yu, Zheng, Rujia, Lou, Yu, Yang, Jiaqi, Tang, Jianghui, Ye, Mao, Hong, Zhengtao, Wu, Jiangchao, Ding, Haonan, Zhang, Yuquan, Sheng, Jianpeng, Lu, Xinjiang, Xu, Pinglong, Lu, Xiongbin, Bai, Xueli, Liang, Tingbo, Zhang, Qi
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6979353489
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