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

• Published in: Nature medicine Vol. 25; no. 9; pp. 1428 - 1441
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2019; Nature Publishing Group
• Subjects: 631/250/2502; 631/250/251; 631/250/580; 631/67/1059; 631/67/580; Animal models; Animals; Anticancer properties; Anxiety; Anxiety - blood; Anxiety - chemically induced; Anxiety - immunology; Anxiety - psychology; Behavior, Animal - physiology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinogens; Carcinogens - toxicity; Cell activation; Clonal deletion; Colorectal Neoplasms - blood; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - psychology; Corticosterone; Corticosterone - blood; Cortisol; Dendritic cells; Dendritic Cells - transplantation; Gene Expression Regulation, Neoplastic; Glucocorticoids; Glucocorticoids - pharmacology; Humans; Hydrocortisone - blood; Immunity; Immunity, Cellular; Immunosurveillance; Infectious Diseases; Interferon; Leukocytes; Lung Neoplasms - blood; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - psychology; Lymphocyte Activation - genetics; Lymphocytes; Lymphocytes T; Metabolic Diseases; Mice; Molecular Medicine; Monitoring, Immunologic - methods; Mood; Neoplasms - chemically induced; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - psychology; Neurosciences; Receptors, Glucocorticoid - antagonists & inhibitors; Signal Transduction - drug effects; Social interactions; Stomach Neoplasms - blood; Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; Stomach Neoplasms - psychology; Stress, Psychological - chemically induced; Stress, Psychological - genetics; Stress, Psychological - immunology; Stress, Psychological - therapy; Supplements; Therapy; Transcription Factors - genetics; Transcription Factors - immunology; Tumors; γ-Interferon; China
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0566-4

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. Stress reduces the effects of various cancer therapies, such as chemotherapy and immunotherapy, in mice; this is mediated, at least partially, through Tsc22d3 upregulation in tumor-infiltrating dendritic cells, which leads to immunosuppression.