title: Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.
abstract: Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. PAPERCLIP.
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA. Electronic address: david.clever@osumc.edu.
authors: David
authors: D
authors: Clever
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
authors: Rahul
authors: R
authors: Roychoudhuri
authors: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA.
authors: Michael G
authors: MG
authors: Constantinides
authors: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA.
authors: Michael H
authors: MH
authors: Askenase
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Madhusudhanan
authors: M
authors: Sukumar
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Christopher A
authors: CA
authors: Klebanoff
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Robert L
authors: RL
authors: Eil
authors: Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
authors: Heather D
authors: HD
authors: Hickman
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Zhiya
authors: Z
authors: Yu
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Jenny H
authors: JH
authors: Pan
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Douglas C
authors: DC
authors: Palmer
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Anthony T
authors: AT
authors: Phan
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: John
authors: J
authors: Goulding
authors: Experimental Transplantation Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors: Luca
authors: L
authors: Gattinoni
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Ananda W
authors: AW
authors: Goldrath
authors: Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA; NIAID Microbiome Program Initiative, NIAID/NIH, Bethesda, MD 20892, USA.
authors: Yasmine
authors: Y
authors: Belkaid
authors: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: restifo@nih.gov.
authors: Nicholas P
authors: NP
authors: Restifo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D006019:Glycolysis / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary* / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D039942:Neuropilin-1 / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology
chemical_list: D039942:Neuropilin-1; D007371:Interferon-gamma; D064828:Prolyl Hydroxylases; D010100:Oxygen