Wang and Cao et al. focused on how TAMs contribute to tumor progression. An immunosuppressive CD19+ macrophage subpopulation, associated with poor clinical outcomes, was enriched in HCC and many other cancer types. These cells exhibited increased levels of PD-L1 and CD73, enhanced mitochondrial oxidation, and deficient phagocytosis. Mechanistically, PAX5 drove mitochondrial biogenesis in CD19+ TAMs, depleting cytosolic Ca2+, leading to lysosomal deficiency and accumulation of PD-L1 and CD73. Targeting CD19+ TAMs with CD19-specific CAR T cells, anti-CD73, or OXPHOS inhibitors enhanced the efficacy of checkpoint blockade therapy in HCC models.
Contributed by Katherine Turner
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 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 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.
Author Info: (1) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory o
Author Info: (1) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (2) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (3) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Biomedical Big Data Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (4) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (5) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Biomedical Big Data Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (6) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (7) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (8) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (9) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (10) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (11) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (12) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (13) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (14) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (15) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University Cancer Center, Hangzhou, China. MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, China. (16) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China. (17) Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University Cancer Center, Hangzhou, China. Life Sciences Institute, Zhejiang University, Hangzhou, China. (18) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (19) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University Cancer Center, Hangzhou, China. MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, China. Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China. The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China. (20) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. liangtingbo@zju.edu.cn. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. liangtingbo@zju.edu.cn. Zhejiang University Cancer Center, Hangzhou, China. liangtingbo@zju.edu.cn. MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, China. liangtingbo@zju.edu.cn. Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn. The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China. liangtingbo@zju.edu.cn. (21) Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. qi.zhang@zju.edu.cn. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. qi.zhang@zju.edu.cn. Zhejiang University Cancer Center, Hangzhou, China. qi.zhang@zju.edu.cn. MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, China. qi.zhang@zju.edu.cn. Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China. qi.zhang@zju.edu.cn. The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China. qi.zhang@zju.edu.cn.
