Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche

被引：203

作者：

Clever, David ^{[1
,2
]}

Roychoudhuri, Rahul ^{[1
,3
]}

Constantinides, Michael G. ^{[4
]}

Askenase, Michael H. ^{[4
]}

Sukumar, Madhusudhanan ^{[1
]}

Klebanoff, Christopher A. ^{[1
,6
,7
]}

Eil, Robert L. ^{[1
]}

Hickman, Heather D. ^{[8
]}

Yu, Zhiya ^{[1
]}

Pan, Jenny H. ^{[1
]}

Palmer, Douglas C. ^{[1
]}

Phan, Anthony T. ^{[9
]}

Goulding, John ^{[9
]}

Gattinoni, Luca ^{[10
]}

Goldrath, Ananda W. ^{[9
]}

Belkaid, Yasmine ^{[4
,5
]}

Restifo, Nicholas P. ^{[1
,11
]}

机构：

[1] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA

[2] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA

[3] Babraham Inst, Lab Lymphocyte Signaling & Dev, Cambridge CB22 3AT, England

[4] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA

[5] NIAID, NIAID Microbiome Program Initiat, NIH, Bethesda, MD 20892 USA

[6] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[8] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA

[9] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA

[10] NCI, Expt Transplantat Immunol Branch, NIH, Bethesda, MD 20892 USA

[11] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA

来源：

CELL | 2016年 / 166卷 / 05期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; DENDRITIC CELLS; METABOLIC CHECKPOINT; EXPRESSION; INDUCTION; DIFFERENTIATION; HOMEOSTASIS; RESPONSES; SUBSETS; MEMORY;

D O I：

10.1016/j.cell.2016.07.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-g-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.

引用

页码：1117 / +

页数：29

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