Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

• Published in: Cell 2016-05, Vol.165 (5), p.1092-1105
• Main Authors: Wang, Weimin, Kryczek, Ilona, Dostál, Lubomír, Lin, Heng, Tan, Lijun, Zhao, Lili, Lu, Fujia, Wei, Shuang, Maj, Tomasz, Peng, Dongjun, He, Gong, Vatan, Linda, Szeliga, Wojciech, Kuick, Rork, Kotarski, Jan, Tarkowski, Rafał, Dou, Yali, Rattan, Ramandeep, Munkarah, Adnan, Liu, J. Rebecca, Zou, Weiping
• Format: Article
• Language: English
• Subjects: animal ovaries; Animals; Antineoplastic Agents - therapeutic use; antiporters; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - metabolism; Cell Culture Techniques; Cell Line, Tumor; Cisplatin - therapeutic use; cysteine; cystine; Drug Resistance, Neoplasm; drug therapy; Female; fibroblasts; Fibroblasts - metabolism; glutamic acid; glutathione; Glutathione - metabolism; Humans; immunotherapy; Interferon-gamma - metabolism; interferons; mechanism of action; metabolism; Mice; Mice, Inbred NOD; Mice, Nude; neoplasm cells; ovarian neoplasms; Ovarian Neoplasms - drug therapy; patients; platinum; transcription (genetics)
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.04.009

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. [Display omitted] •Fibroblasts diminish platinum content in cancer cells, resulting in drug resistance•GSH and cysteine released by fibroblasts contribute to platinum resistance•T cells alter fibroblast GSH and cystine metabolism and abolish the resistance•Fibroblasts and CD8+ T cells associate with patient chemotherapy response T cells abrogate chemoresistance of ovarian tumors by altering the metabolism of stromal fibroblasts in the tumor microenvironment, revealing a point of intersection for combined immunotherapy and chemotherapy in cancer treatment.