Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

Weimin Wang; Ilona Kryczek; Lubomír Dostál; Heng Lin; Lijun Tan; Lili Zhao; Fujia Lu; Shuang Wei; Tomasz Maj; Dongjun Peng; Gong He; Linda Vatan; Wojciech Szeliga; Rork Kuick; Jan Kotarski; Rafał Tarkowski; Yali Dou; Ramandeep Rattan; Adnan Munkarah; J. Rebecca Liu; Weiping Zou

doi:10.1016/j.cell.2016.04.009

Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

Weimin Wang, Ilona Kryczek, Lubomír Dostál, Heng Lin, Lijun Tan, Lili Zhao, Fujia Lu, Shuang Wei, Tomasz Maj, Dongjun Peng, Gong He, Linda Vatan, Wojciech Szeliga, Rork Kuick, Jan Kotarski, Rafał Tarkowski, Yali Dou, Ramandeep Rattan, Adnan Munkarah, J. Rebecca Liu^*Weiping Zou

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

328 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	1092-1105
Number of pages	14
Journal	Cell
Volume	165
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.04.009
State	Published - May 19 2016

Funding

This work is supported (in part) by the Department of Defense ( W81XWH-10-1-0865 ), the NIH grants ( CA123088 , CA099985 , CA156685 , CA171306 , CA190176 , CA193136 , and 5P30CA46592 ), the Ovarian Cancer Research Fund , and Marsha Rivkin Center for Ovarian Cancer Research . This work utilized Metabolomics Core Services supported by grant U24 DK097153 of NIH Common Funds Project to the University of Michigan. We thank Kathleen Cho for her intellectual support. We thank D. Postiff, M. Vinco, R. Craig, and J. Barikdar for their assistance. We thank Chunhai Ruan and Charles F. Burant at the Metabolomics Core, Ted J. Huston at the Department of Earth and Environmental Sciences, Peng Huang at the University of Texas, and Stephen B. Howell at the University of California San Diego for their support. We appreciate the support from Barbara and Don Leclair.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2016.04.009

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Wang, 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., ... Zou, W. (2016). Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell, 165(5), 1092-1105. https://doi.org/10.1016/j.cell.2016.04.009

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title = "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 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.",

author = "Weimin Wang and Ilona Kryczek and Lubom{\'i}r Dost{\'a}l and Heng Lin and Lijun Tan and Lili Zhao and Fujia Lu and Shuang Wei and Tomasz Maj and Dongjun Peng and Gong He and Linda Vatan and Wojciech Szeliga and Rork Kuick and Jan Kotarski and Rafa{\l} Tarkowski and Yali Dou and Ramandeep Rattan and Adnan Munkarah and Liu, {J. Rebecca} and Weiping Zou",

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year = "2016",

month = may,

day = "19",

doi = "10.1016/j.cell.2016.04.009",

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Wang, 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, Liu, JR & Zou, W 2016, 'Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer', Cell, vol. 165, no. 5, pp. 1092-1105. https://doi.org/10.1016/j.cell.2016.04.009

TY - JOUR

T1 - Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

AU - Wang, Weimin

AU - Kryczek, Ilona

AU - Dostál, Lubomír

AU - Lin, Heng

AU - Tan, Lijun

AU - Zhao, Lili

AU - Lu, Fujia

AU - Wei, Shuang

AU - Maj, Tomasz

AU - Peng, Dongjun

AU - He, Gong

AU - Vatan, Linda

AU - Szeliga, Wojciech

AU - Kuick, Rork

AU - Kotarski, Jan

AU - Tarkowski, Rafał

AU - Dou, Yali

AU - Rattan, Ramandeep

AU - Munkarah, Adnan

AU - Liu, J. Rebecca

AU - Zou, Weiping

PY - 2016/5/19

Y1 - 2016/5/19

N2 - 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 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.

AB - 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 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.

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AN - SCOPUS:84964637801

SN - 0092-8674

VL - 165

SP - 1092

EP - 1105

JO - Cell

JF - Cell

IS - 5

ER -

Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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