Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.
Wang W, Kryczek I, Dostal L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, He G, Vatan L, Szeliga W, Kuick R, Kotarski J, Tarkowski R, Dou Y, Rattan R, Munkarah A, Liu JR, and Zou W. Effector t cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 2016; 165(5):1092-1105.
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.
Medical Subject Headings
Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Fibroblasts; Glutathione; Humans; Interferon-gamma; Mice; Mice, Inbred NOD; Mice, Nude; Ovarian Neoplasms