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Stress–Glucocorticoid–TSC22D3 Axis Compromises Therapy-Induced Antitumor Immunity

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Stress–Glucocorticoid–TSC22D3 Axis Compromises Therapy-Induced Antitumor Immunity ARTICLES https://doi.org/10.1038/s41591-019-0566-4 Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity Heng Yang1,2,22, Lin Xia1,2,22, Jian Chen3,22, Shuqing Zhang1,2, Vincent Martin4, Qingqing Li1,2, Shangqing Lin1,2, Jinfeng Chen1,2, Joseph Calmette5, Min Lu! !6, Lingyi Fu7, Jie Yang7, Zhizhong Pan7, Kuai Yu7, Jingjing He7, Eric Morand! !8, Géraldine Schlecht-Louf! !5, Roman Krzysiek5,9, Laurence Zitvogel1,2,10,11,12, Boxi Kang! !13, Zeming Zhang! !13, Andrew Leader14, Penghui Zhou7, Laurence Lanfumey! !4, Minxin Shi3, Guido Kroemer! !1,2,15,16,17,18,19,20,21,23* and Yuting Ma! !1,2,23* 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 inter- feron (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 mod- els, 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. atients with cancer often rationalize their diseases as a conse- psychosocial stress on the outcome of cancer treatment has not been quence of adverse life experiences, which contrasts with large investigated in detail. prospective studies that have failed to establish such a correla- Before the advent of immunotherapy, cancer was usually treated P1 tion . In sharp opposition, there is overwhelming epidemiological by surgery, chemotherapy, radiotherapy and targeted therapies. The evidence that dietary factors, in particular overweight and obesity, goal of this treatment was reduction of the proliferation of malig- can influence the morbidity and mortality of a number of distinct nant cells (cytostasis) or elimination of them by activating cell-death cancers2, a fact that is often denied at the individual, subjective level. programs (cytotoxicity). The overarching logic of this approach was Beyond the non-objectivity in the patients’ appreciation of their consideration of neoplasm as a disease caused solely by malignant mental and bodily selves, cancer is a highly heterogeneous disease cells, meaning that the therapeutic agents needed to target cancer in which the (epi)genetic makeup of malignant cells as well as the cells themselves5. In this perspective, which simplifies cancer to a particularities of the tumor microenvironment make each individ- cell-biology problem, there is no space to explain how psychosocial ual case unique3. For these reasons, psychological factors, including and neuroendocrine factors might affect the efficacy of chemother- mental stress, may be difficult to relate to the incidence, progression apy or radiotherapy. and therapeutic response of malignant diseases. Although one large Recent work, however, has led a radical change in the view on meta-analysis (on 163,363 individuals) revealed that self-reported how therapeutic success (that is, long-term control, or even a cure, psychological-distress scores are epidemiologically linked to can- of the disease) may be achieved by cancer therapies. Indeed, when cer-related mortality (in particular to colorectal, prostate, pancre- the effects of treatment last beyond treatment discontinuation, atic and esophageal cancer, as well as to leukemia)4, the impact of these might be attributed to the induction of an anticancer immune 1Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. 2Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. 3The Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China. 4INSERM UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, Paris, France. 5UMR996, Inflammation, Chemokines and Immunopathology, INSERM, Université Paris-Sud, Université Paris-Saclay, Clamart, France. 6State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. 7State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. 8Clinical Sciences, Monash University, Monash Medical Centre, Clayton, Victoria, Australia. 9Laboratoire d’Immunologie Biologique, CHU du Kremlin Bicêtre, AP-HP, Paris, France. 10INSERM U1015, Gustave Roussy Cancer Campus (GRCC), Villejuif, France. 11Université Paris-Saclay, Villejuif, France. 12Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. 13BIOPIC, Beijing Advanced Innovation Centre for Genomics, and School of Life Sciences, Peking University, Beijing, China. 14Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 15Université de Paris, Paris, France. 16Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. 17Institut National de la Santé et de la Recherche Médicale U1138, Paris, France. 18Sorbonne Université, Paris, France. 19Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. 20Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique – Hopitaux de Paris, Paris, France. 21Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden. 22These authors contributed equally: Heng Yang, Lin Xia, Jian Chen. 23These authors jointly supervised this work: Guido Kroemer and Yuting Ma. *e-mail: [email protected]; [email protected] 1428 NATURE MEDICINE | VOL 25 | SEPTEMBER 2019 | 1428–1441 | www.nature.com/naturemedicine NATURE MEDICINE ARTICLES response, meaning that therapeutic intervention with drugs or activities in the sucrose splash test (Extended Data Fig. 1i) and irradiation has converted the tumor into its own vaccine6. This avoidance of social interactions (Extended Data Fig. 1j–l). We has been exemplified experimentally and clinically for several suc- determined the effect of SD on urethane-induced non-small-cell cessful chemotherapeutic agents, such as anthracyclines and oxali- lung cancer (NSCLC) in mice, in which we scored the spontaneous platin (OXA), that are widely used for the treatment of mammary development of tumors, as well as the response to chemotherapy and colorectal carcinomas, respectively. Anthracyclines and OXA with OXA, an ICD inducer (Fig. 1d), using micro-CT. SD in mice stimulate a type of cancer-cell death that is immunogenic owing to caused an increase in the number and tumor burden (tumor size in danger-associated molecular patterns (DAMPs) that are released mm2) of lung neoplasias relative to non-stressed controls. Although from malignant cells or are exposed on their surface to attract DC OXA-based chemotherapy reduced tumor mass and mean tumor precursors into the tumor bed, trigger the transfer of portions of size in unstressed mice, this therapeutic effect was largely compro- the malignant cell into an immature DC, stimulate DC maturation mised in SD-conditioned mice (Fig. 1e–g). Moreover, histopatho- and finally induce cross-presentation of tumor-associated antigens logical examination suggested that SD facilitated the formation to cytotoxic T lymphocytes (CTLs). Such tumor-antigen-specific of adenoma and adenocarcinoma and diminished the capacity of CTLs produce IFN-γ and then mediate the long-term effects of che- OXA to eradicate adenocarcinomas (Fig. 1h,i). We also explored the motherapy with respect to tumor-growth retardation7–9. impact of SD on colorectal cancers induced by a combination of Immunity is organized in a systemic rather than local fashion azoxymethane (AOM), a genotoxic carcinogen, and dextran sodium (the ‘immune system’) and is known to be profoundly influenced by sulfate (DSS), a pro-inflammatory and colitis-inducing agent neuroendocrine factors, including multiple neurotransmitters, neu- (Fig. 1j). SD consistently increased the number and size of colorectal ropeptides and hormones (such as glucocorticoids that increase in tumors. Moreover, OXA-based chemotherapy reduced the number the context of psychological distress)10–12, establishing functionally of detectable neoplasias in control mice, yet failed to do so in the SD important neuro–immune interactions13,14. Given the importance of group (Fig. 1k–m). It is noteworthy that SD procedures caused sur- immune effectors, such as DCs and CTLs, for the efficacy of immu- vival disadvantage in mice that received either PBS or OXA, indi- nogenic cell death (ICD)-inducing chemotherapies, this creates a cating that they had increased vulnerability to colon carcinogenesis possible mechanistic link between mental factors and
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