Scolaro et al. showed that cytidine deaminase (CDA) was upregulated in several immunotherapy-resistant tumors and contributed to the uridine diphosphate (UDP) pool in the extracellular milieu. Activation of the UDP receptor P2Y6 recruited immunosuppressive TAMs and suppressed cytotoxic T cell infiltration and responses to anti-PD-1 treatment. In human tumors, high CDA levels in cancer cells correlated with increased TAMs and lower cytotoxic T cells. Genetic or pharmacologic CDA inhibition disrupted TAM-mediated immunosuppression, promoted cytotoxic T-cell infiltration, and sensitized tumors to anti-PD-1 therapy in resistant PDAC and melanoma models.
Contributed by Shishir Pant
ABSTRACT: Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y(6). Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y(6) in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDA(high) cancer cells match with T cell cytotoxicity dysfunction and P2RY6(high) TAMs. Overall, we suggest CDA and P2Y(6) as potential targets for cancer immunotherapy.
Author Info: (1) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology
Author Info: (1) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (2) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (3) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universitt Dresden, Dresden, Germany. (4) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. Life and Health Sciences Research Institute, School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal. ICVS/3B's-PT Government Associate Laboratory, Braga/Guimares, Portugal. (5) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (6) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (7) Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. (8) Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore. (9) Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (10) Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. (11) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (12) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (13) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. Department of Medical-Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy. (14) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (15) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (16) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (17) Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium. Metabolomics Core Facility, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (18) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (19) Unicle Biomedical Data Science, Leuven, Belgium. (20) State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. (21) State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. (22) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (23) Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. (24) Translation Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. (25) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (26) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (27) Unicle Biomedical Data Science, Leuven, Belgium. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (28) Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium. Metabolomics Core Facility, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (29) Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. (30) NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. (31) Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. (32) Translation Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. (33) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (34) Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. (35) Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (36) Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore. (37) Department of Visceral Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium. (38) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. massimiliano.mazzone@kuleuven.vib.be. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. massimiliano.mazzone@kuleuven.vib.be.
