Effector CD8+ T cells abrogate fibroblasts-mediated chemoresistance in ovarian cancer (TUM2P.1007)

Abstract

Abstract Tumor infiltrating effector CD8+ T cells have been described to play a major role in antitumoral activity and to be a favorable prognostic factor in ovarian cancer. The strategies of immunotherapy to improve effector T cells response have also shown potential clinical benefit in subset of ovarian cancer patients. Currently platinum-based chemotherapy is still the most active regimen for ovarian cancer treatment. However, the therapeutic resistance is a major challenge to limit the therapeutic efficiency. Here we found primary fibroblasts isolated from ovarian tumor speciman could induce resistance against cisplatin in cancer cells when the two cell types were co-cultured in vitro or co-inoculated in vivo. Activated CD8+ T cells abolished fibroblasts-mediated cisplatin resistance through IFNγ secretion. Next, we found fibroblasts induced cisplatin resistance through increasing intracellular Glutathione (GSH) level and reducing the cisplatin accumulation in cancer cells. We also identified both intact GSH and Cysteine released by fibroblasts contributed to cisplatin resistance in cancer cells. IFNγ producted by activated CD8+ T cells promoted fibroblasts extracellular GSH degradation through up-regulation of Gamma-glutamyl transpeptidase, and also diminished Cysteine generation by fibroblasts through down-regulation of System xc⁻ cystine/glutamate antiporter.These date implicate effector T cells immunotherapy as a powerful regimen to overcome the resistance to chemotherapy.