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

被引：304

作者：

Yang, Heng ^{[1
,2
,3
]}

Xia, Lin ^{[1
,2
,3
]}

Chen, Jian ^{[4
]}

Zhang, Shuqing ^{[1
,2
,3
]}

Martin, Vincent ^{[5
]}

Li, Qingqing ^{[1
,2
,3
]}

Lin, Shangqing ^{[1
,2
,3
]}

Chen, Jinfeng ^{[1
,2
,3
]}

Calmette, Joseph ^{[6
]}

Lu, Min ^{[7
]}

Fu, Lingyi ^{[8
]}

Yang, Jie ^{[8
]}

Pan, Zhizhong ^{[8
]}

Yu, Kuai ^{[8
]}

He, Jingjing ^{[8
]}

Morand, Eric ^{[9
]}

Schlecht-Louf, Geraldine ^{[6
]}

Krzysiek, Roman ^{[6
,10
]}

Zitvogel, Laurence ^{[1
,2
,3
,11
,12
,13
]}

Kang, Boxi ^{[14
,15
]}

Zhang, Zeming ^{[14
,15
]}

Leader, Andrew ^{[16
]}

Zhou, Penghui ^{[8
]}

Lanfumey, Laurence ^{[5
]}

Shi, Minxin ^{[4
]}

Kroemer, Guido ^{[1
,2
,3
,17
,18
,19
,20
,21
,22
,23
]}

Ma, Yuting ^{[1
,2
,3
]}

机构：

[1] Chinese Acad Med Sci, Inst Basic Med Sci, Ctr Syst Med, Beijing, Peoples R China

[2] Peking Union Med Coll, Beijing, Peoples R China

[3] Suzhou Inst Syst Med, Suzhou, Jiangsu, Peoples R China

[4] Nantong Univ, Nantong Tumor Hosp, Affiliated Tumor Hosp, Nantong, Jiangsu, Peoples R China

[5] Univ Paris 05, INSERM, UMR S894, Ctr Psychiat & Neurosci, Paris, France

[6] Univ Paris Saclay, Univ Paris Sud, INSERM, UMR996,Inflammat Chemokines & Immunopathol, Clamart, France

[7] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom,Shanghai Inst Hematol, Shanghai, Peoples R China

[8] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol Southern China, Guangzhou, Guangdong, Peoples R China

[9] Monash Univ, Monash Med Ctr, Clin Sci, Clayton, Vic, Australia

[10] CHU Kremlin Bicetre, AP HP, Lab Immunol Biol, Paris, France

[11] Gustave Roussy Canc Campus, U1015, INSERM, Villejuif, France

[12] Univ Paris Saclay, Villejuif, France

[13] Ctr Clin Invest Biotherapies Canc CICBT 1428, Villejuif, France

[14] Peking Univ, Beijing Adv Innovat Ctr Genom, BIOPIC, Beijing, Peoples R China

[15] Peking Univ, Sch Life Sci, Beijing, Peoples R China

[16] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA

[17] Univ Paris, Paris, France

[18] Ctr Rech Cordeliers, Equipe 11 Labellisee Ligue Natl Canc, Paris, France

[19] INSERM, U1138, Paris, France

[20] Sorbonne Univ, Paris, France

[21] Gustave Roussy Canc Campus, Metabol & Cell Biol Platforms, Villejuif, France

[22] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France

[23] Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Stockholm, Sweden

来源：

NATURE MEDICINE | 2019年 / 25卷 / 09期

关键词：

INDUCED LEUCINE-ZIPPER; DEPRESSION-LIKE BEHAVIORS; DENDRITIC CELLS; SOCIAL DEFEAT; CANCER; CHEMOTHERAPY; ACTIVATION; FLUOXETINE; STRESS; GLUCOCORTICOIDS;

D O I：

10.1038/s41591-019-0566-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-gamma(+) 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.

引用

页码：1428 / +

页数：31

共 60 条

[1]

SurvExpress: An Online Biomarker Validation Tool and Database for Cancer Gene Expression Data Using Survival Analysis [J].