1. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche
- Author
-
Jenny H. Pan, Zhiya Yu, Anthony T. Phan, Heather D. Hickman, Madhusudhanan Sukumar, David Clever, Nicholas P. Restifo, Michael H. Askenase, Yasmine Belkaid, Luca Gattinoni, Douglas C. Palmer, Robert L. Eil, Christopher A. Klebanoff, Ananda W. Goldrath, Michael G. Constantinides, Rahul Roychoudhuri, and John Goulding
- Subjects
0301 basic medicine ,Adoptive cell transfer ,Effector ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,Immune system ,Circulating tumor cell ,Antigen ,hemic and lymphatic diseases ,Immunology ,Cancer cell ,medicine ,CD8 - Abstract
Summary 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 (T reg ) cell induction, and restrain CD8 + T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary T reg 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
- Published
- 2016