Journal
CELL
Volume 165, Issue 5, Pages 1092-1105Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.04.009
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Funding
- Department of Defense [W81XWH-10-1-0865]
- NIH [CA123088, CA099985, CA156685, CA171306, CA190176, CA193136, 5P30CA46592, U24 DK097153]
- Ovarian Cancer Research Fund
- Marsha Rivkin Center for Ovarian Cancer Research
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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.
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