中国医学科学院北京协和医学院苏州系统医学研究所马瑜婷和Guido Kroemer等研究人员合作，揭示了压力-糖皮质激素- TSC22D3信号轴损害治疗引起的抗肿瘤免疫。相关论文2019年9月9日发表在《自然—医学》上。

研究人员观察到社交失败导致小鼠焦虑样行为，并抑制致治疗反应，包括癌物诱导的瘤形成和可移植肿瘤。应激升高的血浆皮质酮和上调糖皮质激素诱导因子Tsc22d3的表达，其阻断树突状细胞（DC）的I型干扰素（IFN）反应和IFN-γ阳性T细胞的活化。同样，在血浆皮质醇水平、循环白细胞中TSC22D3表达和癌症患者的消极情绪之间发现了密切的相关性。在鼠模型中，外源性糖皮质激素注射或DC中Tsc22d3的强制表达足以消除对肿瘤的治疗控制。施用糖皮质激素受体拮抗剂或DC特异性Tsc22d3缺失逆转了应激或糖皮质激素补充剂对治疗结果的负面影响。总之，这些结果表明，应激诱导的糖皮质激素激增和Tsc22d3上调可以破坏治疗引起的抗癌免疫监视。压力会降低小鼠中各种癌症疗法（如化疗和免疫疗法）的效果；这至少部分是通过肿瘤浸润的树突细胞中的Tsc22d3上调介导的，从而导致免疫抑制。

据介绍，长期以来人们一直怀疑心理困扰会影响癌症的发病率和死亡率。目前尚不清楚压力是否以及如何影响抗癌疗法的疗效。

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马瑜婷

马瑜婷，中国医学科学院北京协和医学院苏州系统医学研究所研究员，博士生导师（北京协和医学院）。研究方向：细胞应激对肿瘤细胞免疫原性的调控机制、细胞应激对免疫细胞发育，分化及功能的调控机制 、精神应激对免疫应答的调控作用（据苏州系统医学研究所）

附：英文原文

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

Author: 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, Graldine Schlecht-Louf, Roman Krzysiek, Laurence Zitvogel, Boxi Kang, Zeming Zhang, Andrew Leader, Penghui Zhou, Laurence Lanfumey, Minxin Shi, Guido Kroemer, Yuting Ma

Issue&Volume: Volume 25 Issue 9

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-+ 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.

DOI: 10.1038/s41591-019-0566-4

Source: https://www.nature.com/articles/s41591-019-0566-4