Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

被引：200

作者：

Muller, Alexander J. ^{[5
]}

Sharma, Madhav D. ^{[2
]}

Chandler, Phillip R. ^{[1
]}

DuHadaway, James B. ^{[5
]}

Everhart, Mary E. ^{[3
]}

Johnson, Buries A., III ^{[3
]}

Kahler, David J. ^{[3
]}

Pihkala, Jeanene ^{[4
]}

Soler, Alejandro Peralta ^{[5
]}

Munn, David H. ^{[2
]}

Prendergast, George C. ^{[5
]}

Mellor, Andrew L. ^{[1
]}

机构：

[1] Med Coll Georgia, Dept Med, Augusta, GA 30912 USA

[2] Med Coll Georgia, Dept Pediat, Augusta, GA 30912 USA

[3] Immunotherapy & Canc Ctr, Augusta, GA 30912 USA

[4] Flow Cytometry Core Facil, Augusta, GA USA

[5] Lankenau Inst Med Res, Wynnewood, PA 19096 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 44期

基金：

美国国家卫生研究院;

关键词：

dendritic cells; T cells; TPA; carcinogenesis; tryptophan;

D O I：

10.1073/pnas.0806173105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN IDCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/lL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO+ pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.

引用

页码：17073 / 17078

页数：6

共 42 条

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