title: Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.
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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lubomír
authors.initials: L
authors.lastname: Dostál
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Fujia
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Maj
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Gong
authors.initials: G
authors.lastname: He
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.affiliation: The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Kotarski
authors.affiliation: The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Tarkowski
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Munkarah
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA; The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rliu@med.umich.edu.
authors.forename: J Rebecca
authors.initials: JR
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA; The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: wzou@med.umich.edu.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007371:Interferon-gamma; D005978:Glutathione; D002945:Cisplatin