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

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 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 programmed cell death 1 ligand 1 (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 Paired Box 5 (PAX5) as a primary driver of up-regulated mitochondrial biogenesis in CD19+ macrophages, which depletes cytoplasmic Ca2+, 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. Tumor-associated macrophages shape cancer’s immunosuppressive microenvironment, but their heterogeneity hampers therapeutic targeting. This study identifies a CD19+ macrophage subset in hepatocellular carcinoma and evaluates strategies to target them for improved immunotherapy.