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${}^{2+}$, 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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