Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.

Fri, 2016-06-24 12:00 -- voskuhlt
TitleEffector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsWang W, Kryczek I, Dostál 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, J Liu R, Zou W
JournalCell
Volume165
Issue5
Pagination1092-105
Date Published2016 May 19
ISSN1097-4172
Abstract

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.

DOI10.1016/j.cell.2016.04.009
Alternate JournalCell
PubMed ID27133165
PubMed Central IDPMC4874853
Grant ListR01 CA152470 / CA / NCI NIH HHS / United States
R01 CA171306 / CA / NCI NIH HHS / United States
R01 CA190176 / CA / NCI NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States