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Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.
Scolaro, Tommaso; Manco, Marta; Pecqueux, Mathieu; Amorim, Ricardo; Trotta, Rosa; Van Acker, Heleen H; Van Haele, Matthias; Shirgaonkar, Niranjan; Naulaerts, Stefan; Daniluk, Jan; Prenen, Fran; Varamo, Chiara; Ponti, Donatella; Doglioni, Ginevra; Ferreira Campos, Ana Margarida; Fernandez Garcia, Juan; Radenkovic, Silvia; Rouhi, Pegah; Beatovic, Aleksandar; Wang, Liwei; Wang, Yu; Tzoumpa, Amalia; Antoranz, Asier; Sargsian, Ara; Di Matteo, Mario; Berardi, Emanuele; Goveia, Jermaine; Ghesquière, Bart; Roskams, Tania; Soenen, Stefaan; Voets, Thomas; Manshian, Bella; Fendt, Sarah-Maria; Carmeliet, Peter; Garg, Abhishek D; DasGupta, Ramanuj; Topal, Baki; Mazzone, Massimiliano.
Afiliación
  • Scolaro T; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Manco M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Pecqueux M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Amorim R; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Trotta R; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Van Acker HH; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Van Haele M; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Shirgaonkar N; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Naulaerts S; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Daniluk J; Life and Health Sciences Research Institute, School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.
  • Prenen F; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • Varamo C; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Ponti D; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Doglioni G; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Ferreira Campos AM; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Fernandez Garcia J; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
  • Radenkovic S; Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
  • Rouhi P; Laboratory for Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Beatovic A; Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium.
  • Wang L; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Wang Y; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Tzoumpa A; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Antoranz A; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Sargsian A; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Di Matteo M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Berardi E; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Goveia J; Department of Medical-Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy.
  • Ghesquière B; Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Roskams T; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • Soenen S; Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Voets T; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • Manshian B; Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Fendt SM; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • Carmeliet P; Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Garg AD; Metabolomics Core Facility, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • DasGupta R; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Topal B; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • Mazzone M; Unicle Biomedical Data Science, Leuven, Belgium.
Nat Cancer ; 5(8): 1206-1226, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38844817
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 P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 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, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Uridina Difosfato / Resistencia a Antineoplásicos / Inmunoterapia Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Uridina Difosfato / Resistencia a Antineoplásicos / Inmunoterapia Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido