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Cell. 2016 Aug 25;166(5):1117-1131.e14. doi: 10.1016/j.cell.2016.07.032.

Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.

Author information

1
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.
2
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.
3
Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA.
4
Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
5
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.
6
Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
7
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
8
Experimental Transplantation Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA.
9
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.
10
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.

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.

PMID:
27565342
PMCID:
PMC5548538
DOI:
10.1016/j.cell.2016.07.032
[Indexed for MEDLINE]
Free PMC Article
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