Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

被引：359

作者：

Wang, Weimin ^{[1
,2
]}

Kryczek, Ilona ^{[2
]}

Dostal, Lubomir ^{[3
]}

Lin, Heng ^{[2
]}

Tan, Lijun ^{[1
]}

Zhao, Lili ^{[4
]}

Lu, Fujia ^{[2
]}

Wei, Shuang ^{[2
]}

Maj, Tomasz ^{[2
]}

Peng, Dongjun ^{[2
]}

He, Gong ^{[1
]}

Vatan, Linda ^{[2
]}

Szeliga, Wojciech ^{[2
]}

Kuick, Rork ^{[4
]}

Kotarski, Jan ^{[5
]}

Tarkowski, Rafal ^{[5
]}

Dou, Yali ^{[6
]}

Rattan, Ramandeep ^{[7
]}

Munkarah, Adnan ^{[7
]}

Liu, J. Rebecca ^{[1
,8
]}

Zou, Weiping ^{[2
,8
,9
,10
]}

机构：

[1] Univ Michigan, Dept Obstet & Gynecol, Sch Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Biostat, Sch Med, Ann Arbor, MI 48109 USA

[5] Med Univ Lublin, Dept Gynecol Oncol & Gynecol 1, PL-20081 Lublin, Poland

[6] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[7] Henry Ford Hlth Syst, Dept Womens Hlth Serv, Detroit, MI 48202 USA

[8] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Grad Program Immunol, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Grad Program Tumor Biol, Ann Arbor, MI 48109 USA

来源：

CELL | 2016年 / 165卷 / 05期

关键词：

IMMUNE CHECKPOINT BLOCKADE; TUMOR MICROENVIRONMENT; ANTITUMOR IMMUNITY; REDUCED SURVIVAL; FIBROBLASTS; CISPLATIN; GLUTATHIONE; METABOLISM; RESISTANCE; RELEVANCE;

D O I：

10.1016/j.cell.2016.04.009

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：

Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8(+) T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8(+) T-cell-derived interferon (IFN)gamma controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyl-transferases and transcriptional repression of system xc(-) cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8(+) T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.

引用

页码：1092 / 1105

页数：14

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