Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity
Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity
复制标题
应激-糖皮质激素-TSC22D3 轴损害治疗诱导的抗肿瘤免疫
DOI：
10.1038/s41591-019-0566-4
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发表时间：
2019-09-01
期刊：
影响因子：
82.9
通讯作者：
Ma, Yuting
中科院分区：
文献类型：
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作者：
Yang, Heng;Xia, Lin;Ma, Yuting
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。压力是否以及如何影响抗癌治疗的疗效在很大程度上仍不清楚。我们观察到，社会挫败导致小鼠的焦虑样行为，并抑制了对致癌物诱导的肿瘤和可移植肿瘤的治疗反应。应激可提高血浆皮质酮水平，上调糖皮质激素诱导因子Tsc22d3的表达，从而阻断树突状细胞(DC)中的I型干扰素反应和干扰素-γ(+)T细胞的激活。类似地，癌症患者的血浆皮质醇水平、循环白细胞中TSC22D3的表达与负面情绪之间也存在密切的相关性。在小鼠模型中，外源性糖皮质激素注射或增强Tsc22d3在DC中的表达足以取消对肿瘤的治疗控制。给予糖皮质激素受体拮抗剂或DC特异性Tsc22d3缺失可逆转应激或补充糖皮质激素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上调可以颠覆治疗诱导的抗癌免疫监视。
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.