Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma

Junli Wang; Wanyue Cao; Jinyan Huang; Yu Zhou; Rujia Zheng; Yu Lou; Jiaqi Yang; Jianghui Tang; Mao Ye; Zhengtao Hong; Jiangchao Wu; Haonan Ding; Yuquan Zhang; Jianpeng Sheng; Xinjiang Lu; Pinglong Xu; Xiongbin Lu; Xueli Bai; Tingbo Liang; Qi Zhang

arXiv · 2503.17738

Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma

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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.

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Junli Wang, Wanyue Cao, Jinyan Huang, Yu Zhou, Rujia Zheng, Yu Lou, Jiaqi Yang, Jianghui Tang, Mao Ye, Zhengtao Hong, Jiangchao Wu, Haonan Ding, Yuquan Zhang, Jianpeng Sheng, Xinjiang Lu, Pinglong Xu, Xiongbin Lu, Xueli Bai, Tingbo Liang, Qi Zhang. 2025-03-22. Tumor-associated CD19$^+$ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma. https://arxiv.org/abs/2503.17738

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