Journal: Nature communications
This study characterizes a distinct, clinically relevant subset of tumor-associated macrophages that express CD19 and are enriched across multiple cancers, with particular prominence in hepatocellular carcinoma (HCC).
Key findings:
- Phenotype and function of CD19+ macrophages
- These macrophages display high expression of PD-L1 and CD73.
- They show enhanced mitochondrial oxidative metabolism.
- Their phagocytic capacity is impaired, consistent with an immunosuppressive role in the tumor microenvironment.
- Therapeutic vulnerability
- Targeting CD19+ macrophages with anti-CD19 CAR T cells suppresses HCC tumor growth in experimental models, supporting the therapeutic potential of depleting this subset.
- Mechanistic driver: PAX5
- PAX5 is identified as a key regulator in these cells, driving mitochondrial biogenesis.
- Increased mitochondrial activity lowers cytoplasmic calcium, leading to lysosomal dysfunction.
- This lysosomal deficiency results in accumulation of CD73 and PD-L1 on macrophages, reinforcing their immunosuppressive phenotype.
- Therapeutic implications
- Inhibition of CD73 or mitochondrial oxidation improves the efficacy of immune checkpoint blockade in HCC models.
- These data support a strategy of targeting CD19+ macrophages—directly (e.g., CAR T) or via metabolic/enzymatic pathways (CD73, mitochondrial oxidation)—to enhance immunotherapy responses in HCC.