Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity

Heng Yang, Lin Xia, Jian Chen, Shuqing Zhang, Vincent Martin, Qingqing Li, Shangqing Lin, Jinfeng Chen, Joseph Calmette, Min Lu, Lingyi Fu, Jie Yang, Zhizhong Pan, Kuai Yu, Jingjing He, Eric Morand, Géraldine Schlecht-Louf, Roman Krzysiek, Laurence Zitvogel, Boxi Kang & 7 others Zeming Zhang, Andrew Leader, Penghui Zhou, Laurence Lanfumey, Minxin Shi, Guido Kroemer, Yuting Ma

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

Original languageEnglish
Pages (from-to)1428-1441
Number of pages14
JournalNature Medicine
Volume25
Issue number9
DOIs
Publication statusPublished - 1 Sep 2019

Cite this

Yang, H., Xia, L., Chen, J., Zhang, S., Martin, V., Li, Q., ... Ma, Y. (2019). Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nature Medicine, 25(9), 1428-1441. https://doi.org/10.1038/s41591-019-0566-4
Yang, Heng ; Xia, Lin ; Chen, Jian ; Zhang, Shuqing ; Martin, Vincent ; Li, Qingqing ; Lin, Shangqing ; Chen, Jinfeng ; Calmette, Joseph ; Lu, Min ; Fu, Lingyi ; Yang, Jie ; Pan, Zhizhong ; Yu, Kuai ; He, Jingjing ; Morand, Eric ; Schlecht-Louf, Géraldine ; Krzysiek, Roman ; Zitvogel, Laurence ; Kang, Boxi ; Zhang, Zeming ; Leader, Andrew ; Zhou, Penghui ; Lanfumey, Laurence ; Shi, Minxin ; Kroemer, Guido ; Ma, Yuting. / Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. In: Nature Medicine. 2019 ; Vol. 25, No. 9. pp. 1428-1441.
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abstract = "Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.",
author = "Heng Yang and Lin Xia and Jian Chen and Shuqing Zhang and Vincent Martin and Qingqing Li and Shangqing Lin and Jinfeng Chen and Joseph Calmette and Min Lu and Lingyi Fu and Jie Yang and Zhizhong Pan and Kuai Yu and Jingjing He and Eric Morand and G{\'e}raldine Schlecht-Louf and Roman Krzysiek and Laurence Zitvogel and Boxi Kang and Zeming Zhang and Andrew Leader and Penghui Zhou and Laurence Lanfumey and Minxin Shi and Guido Kroemer and Yuting Ma",
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Yang, H, Xia, L, Chen, J, Zhang, S, Martin, V, Li, Q, Lin, S, Chen, J, Calmette, J, Lu, M, Fu, L, Yang, J, Pan, Z, Yu, K, He, J, Morand, E, Schlecht-Louf, G, Krzysiek, R, Zitvogel, L, Kang, B, Zhang, Z, Leader, A, Zhou, P, Lanfumey, L, Shi, M, Kroemer, G & Ma, Y 2019, 'Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity', Nature Medicine, vol. 25, no. 9, pp. 1428-1441. https://doi.org/10.1038/s41591-019-0566-4

Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. / Yang, Heng; Xia, Lin; Chen, Jian; Zhang, Shuqing; Martin, Vincent; Li, Qingqing; Lin, Shangqing; Chen, Jinfeng; Calmette, Joseph; Lu, Min; Fu, Lingyi; Yang, Jie; Pan, Zhizhong; Yu, Kuai; He, Jingjing; Morand, Eric; Schlecht-Louf, Géraldine; Krzysiek, Roman; Zitvogel, Laurence; Kang, Boxi; Zhang, Zeming; Leader, Andrew; Zhou, Penghui; Lanfumey, Laurence; Shi, Minxin; Kroemer, Guido; Ma, Yuting.

In: Nature Medicine, Vol. 25, No. 9, 01.09.2019, p. 1428-1441.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity

AU - Yang, Heng

AU - Xia, Lin

AU - Chen, Jian

AU - Zhang, Shuqing

AU - Martin, Vincent

AU - Li, Qingqing

AU - Lin, Shangqing

AU - Chen, Jinfeng

AU - Calmette, Joseph

AU - Lu, Min

AU - Fu, Lingyi

AU - Yang, Jie

AU - Pan, Zhizhong

AU - Yu, Kuai

AU - He, Jingjing

AU - Morand, Eric

AU - Schlecht-Louf, Géraldine

AU - Krzysiek, Roman

AU - Zitvogel, Laurence

AU - Kang, Boxi

AU - Zhang, Zeming

AU - Leader, Andrew

AU - Zhou, Penghui

AU - Lanfumey, Laurence

AU - Shi, Minxin

AU - Kroemer, Guido

AU - Ma, Yuting

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

AB - Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

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