2. Academic Validation
  3. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity

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

  • Nat Med. 2019 Sep;25(9):1428-1441. doi: 10.1038/s41591-019-0566-4.
Heng Yang  # 1 2,  Lin Xia  # 1 2,  Jian Chen  # 3,  Shuqing Zhang 1 2,  Vincent Martin 4,  Qingqing Li 1 2,  Shangqing Lin 1 2,  Jinfeng Chen 1 2,  Joseph Calmette 5,  Min Lu 6,  Lingyi Fu 7,  Jie Yang 7,  Zhizhong Pan 7,  Kuai Yu 7,  Jingjing He 7,  Eric Morand 8,  Géraldine Schlecht-Louf 5,  Roman Krzysiek 5 9,  Laurence Zitvogel 1 2 10 11 12,  Boxi Kang 13,  Zeming Zhang 13,  Andrew Leader 14,  Penghui Zhou 7,  Laurence Lanfumey 4,  Minxin Shi 3,  Guido Kroemer  # 15 16 17 18 19 20 21 22 23,  Yuting Ma  # 24 25
Affiliations

Affiliations

  • 1 Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.
  • 3 The Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China.
  • 4 INSERM UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, Paris, France.
  • 5 UMR996, Inflammation, Chemokines and Immunopathology, INSERM, Université Paris-Sud, Université Paris-Saclay, Clamart, France.
  • 6 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 7 State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 8 Clinical Sciences, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.
  • 9 Laboratoire d'Immunologie Biologique, CHU du Kremlin Bicêtre, AP-HP, Paris, France.
  • 10 INSERM U1015, Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
  • 11 Université Paris-Saclay, Villejuif, France.
  • 12 Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
  • 13 BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China.
  • 14 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 15 Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. kroemer@orange.fr.
  • 16 Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. kroemer@orange.fr.
  • 17 Université de Paris, Paris, France. kroemer@orange.fr.
  • 18 Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. kroemer@orange.fr.
  • 19 Institut National de la Santé et de la Recherche Médicale U1138, Paris, France. kroemer@orange.fr.
  • 20 Sorbonne Université, Paris, France. kroemer@orange.fr.
  • 21 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. kroemer@orange.fr.
  • 22 Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique - Hopitaux de Paris, Paris, France. kroemer@orange.fr.
  • 23 Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. kroemer@orange.fr.
  • 24 Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. yuting_ma1984@163.com.
  • 25 Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. yuting_ma1984@163.com.
  • # Contributed equally.
PMID: 31501614 DOI: 10.1038/s41591-019-0566-4
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.

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