Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 May 3

PMID 27133165

Citations 231

Authors

Weimin Wang

Ilona Kryczek

Lubomir Dostal

Heng Lin

Lijun Tan

Lili Zhao

Fujia Lu

Shuang Wei

Tomasz Maj

Dongjun Peng

Gong He

Linda Vatan

Wojciech Szeliga

Rork Kuick

Jan Kotarski

Rafal Tarkowski

Yali Dou

Ramandeep Rattan

Adnan Munkarah

J Rebecca Liu

Weiping Zou

Affiliations

Soon will be listed here.

Abstract

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)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases 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.

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