Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma
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, 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.
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Cite
@article{arxiv.2503.17738,
title = {Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma},
author = {Junli Wang and Wanyue Cao and Jinyan Huang and Yu Zhou and Rujia Zheng and Yu Lou and Jiaqi Yang and Jianghui Tang and Mao Ye and Zhengtao Hong and Jiangchao Wu and Haonan Ding and Yuquan Zhang and Jianpeng Sheng and Xinjiang Lu and Pinglong Xu and Xiongbin Lu and Xueli Bai and Tingbo Liang and Qi Zhang},
journal= {arXiv preprint arXiv:2503.17738},
year = {2025}
}
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7 figures