| Literature DB >> 27133165 |
Weimin Wang1, Ilona Kryczek2, Lubomír Dostál3, Heng Lin2, Lijun Tan4, Lili Zhao5, Fujia Lu2, Shuang Wei2, Tomasz Maj2, Dongjun Peng2, Gong He4, Linda Vatan2, Wojciech Szeliga2, Rork Kuick5, Jan Kotarski6, Rafał Tarkowski6, Yali Dou7, Ramandeep Rattan8, Adnan Munkarah8, J Rebecca Liu9, Weiping Zou10.
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.Entities:
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Year: 2016 PMID： 27133165 PMCID： PMC4874853 DOI： 10.1016/j.cell.2016.04.009
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582