Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

Abstract

SUMMARY 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 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.

Meeting Report From the 2016 11th Biennial Ovarian Cancer Research Symposium

“…These results, taken together with the recent report by Wang et al 13 indicating the stromal-derived glutathione in chemotherapy resistance, 13 point to molecular mechanisms regulating redox states in cancer cells and their effect on cancer progression and chemotherapy resistance.…”

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

“…Human peripheral blood T cells were stimulated for 5 days with anti-CD3 and anti-CD28 in the presence of IFN-γ-activated DCs, macrophages, or fixed primary ovarian cancer cells (41,42). Antihuman PD-L1 and isotype controls were added at the beginning of culture (26).…”

Increased STAT1 Expression in High Grade Serous Ovarian Cancer Is Associated With a Better Outcome

“…27 It was recently shown that CD8 + T cellYderived INF-F controls fibroblast glutathione and cysteine via the JAK/STAT1 pathway, diminishing nuclear accumulation of platinum in ovarian cancer cells. 28 Studies on signal transduction pathways and the key role of molecular markers that are related to resistance/sensitivity to chemotherapy in ovarian epithelial tumor are crucial. Gene expression is regulated by cytokines that control the immune response in tumor tissue.…”