压力激素对抗肿瘤免疫应答的调控机制

Upon experiencing external stress, the hypothalamic-pituitary-adrenal (HPA) axis is activated to secret stress hormones in organisms, which consequently modulate several important physiological functions. Stress hormones include glucocorticoid and adrenaline, whose secretion is under strict regulatory control. However, mental stress can over-activate the secretion of stress hormones. A large proportion of cancer patient have the concomitant symptoms of anxiety or depression, while chemotherapy can further aggravate these symptoms. Clinical observations suggest a correlation between anxiety/depression and a poor prognosis of cancer. Anti-tumor immune responses are essential for the optimal therapeutic effect of chemotherapy. It has been reported that stress hormone can regulate the function of immune cells. However, it remains unclear whether stress induced hormones could affect anti-tumor immune response and the efficacy of chemotherapy. Glucocorticoid is commonly combined with chemotherapeutic drugs in standard cancer therapy regimens. Whether the administration of exogenous stress hormone can influence therapeutic effect hasn’t been explored. We plan to use mouse acute/ chronic stress models and cancer therapy models to answer these questions. By applying flow cytometry, immunohistochemistry, transcriptome analysis, gene-modified mice and CRISPR-based gene editing, we will demonstrate the impact of stress hormones on anti-tumor immune responses and tumor cell immunogenicity. We will also explore the related molecular mechanisms. This study will provide novel therapeutic strategies for cancer patients with mental stress symptoms. Also, it will have reference values for the rational use of glucocorticoid in clinical cancer management.

当遭遇外界压力时，生物体可活化下丘脑-垂体-肾上腺轴，通过分泌压力激素调控多种生理机能，形成反馈性应答。压力激素包括糖皮质激素和肾上腺素等，其分泌受到精密的调控。但精神障碍可导致压力激素分泌的过度活跃。肿瘤患者多伴发焦虑抑郁，化疗可加重这些症状，且与肿瘤的不良预后有关。抗肿瘤免疫应答是发挥化疗最佳效果的关键，而免疫细胞功能可受压力激素调控。目前，尚不清楚压力诱导的激素能否影响抗肿瘤免疫应答及肿瘤治疗效果。糖皮质激素与化疗药物的联用是常用的临床化疗方案，外源性压力激素能否影响化疗效果有待解答。申请人计划借助小鼠的急性和慢性的压力模型及肿瘤治疗模型，通过流式细胞术，免疫组化，转录组测序，基因改造小鼠和CRISPR基因编辑技术，系统性的阐述压力激素对抗肿瘤免疫应答，肿瘤细胞免疫原性的影响及相关分子机制。这项研究将为精神应激的肿瘤患者治疗提供新策略，也为压力激素在肿瘤治疗中的合理使用提供参考。

背景：朴素的自然观认为，精神应激可能会影响肿瘤的发生、进展与治疗效果。然而，由于干扰因素众多，设定对照人群困难，肿瘤类型、分期及治疗方案的差异，大规模的临床观察、流行病学研究、以及相关荟萃分析的结论常常有较大分歧。借助小鼠模型，稳定诱导精神应激并配合精准的量化测试，有望验证精神压力与肿瘤病程、疗效之间是否存在因果联系，也为相关分子机制的探索提供了可能。.内容：我们借助小鼠重复社交挫折（SD）模型、急性束缚（AR）模型稳定诱导小鼠的精神压力，并通过开场、明暗盒、仪容整理、社交互作等多种行为学测试量化小鼠的焦虑及抑郁表型。在小鼠移植瘤、致癌物诱导的原发瘤的化疗和肿瘤疫苗模型中，比较SD小鼠与对照小鼠肿瘤生长及治疗效果的差异。通过系统性分析肿瘤微环境、外周血免疫细胞及效应分子的谱图，压力激素及神经递质的浓度与小鼠行为学表型的相关性，探索精神压力对抗肿瘤免疫的影响、分子调控机制、以及有助于改善SD小鼠肿瘤疗效的干预策略。.结果与数据：SD组小鼠的肺癌、肠癌及骨肉瘤对化疗、肿瘤疫苗及免疫治疗的响应显著降低。SD处理可使外周血中皮质酮水平显著升高，血清素及去甲肾上腺素水平显著降低。SD不仅可诱导肿瘤微环境中的局部免疫抑制，抑制Th1/Tc1应答，重编程肿瘤内DC的转录组，还可以造成全身性的免疫抑制，阻滞外周血中多种细胞因子、趋化因子的表达。SNRI类抗抑郁药可有效缓解SD小鼠的焦虑症状，但无法改善化疗效果。而GR拮抗剂可明显的改善小鼠的焦虑表型、化疗、肿瘤疫苗及免疫治疗的效果。.科学意义：本研究明确阐述了精神应激可加速小鼠肿瘤的发生和进展，并显著抑制化疗及免疫治疗效果；证实了精神应激可导致压力激素皮质酮的持续升高，并通过结合GR引发局部及系统性的免疫抑制。相关工作从“精神应激调控抗肿瘤免疫”的全新角度深入探索了神经内分泌系统与免疫系统交互作用的分子机制，并为寻找普适性的免疫治疗靶点开辟了新策略。