慢性心理应激对放疗后肿瘤免疫微环境的影响及其机制研究

Radiation therapy is one of the main therapeutic strategies for patients with cancers. Unfortunately, immunosuppression signaling pathways such as the PD-1/PD-L1 axis has largely restrained the effect of radiotherapy. It is found that cancer patients are frequently under a chronic stress status, which could elevate levels of stress-related hormones like norepinephrine (NE). Studies have found that beta-blocker use is associated with improved survival outcomes in cancer patients treated with definitive radiation therapy and its mechanisms have yet to be elucidated. In our previous study, it was observed that NE could induce the expression of HIF-1α by activating the beta-adrenergic receptor, thus facilitating the downstream PD-1/PD-L1 axis. The PD-L1/PD-1 axis has been characterized as a potent inhibitor of T cell mediated specific adaptive immunity, particularly through inhibition of effector T cell function. Therefore, we speculate that under the state of chronic stress in vivo, NE could suppress the function of the immune system through the β-AR---HIF-1α---PD-1/ PD-L1 signal pathway. On the contrary, beta-blocker could block this process and improve the efficacy of anti-tumor immunity after radiotherapy. In this project, we plan to build tumor-bearing mice models to mimic the status of high levels of NE in cancer patients, to explore the effects and the underlying mechanisms of chronic stress on the tumor immune microenvironment after radiotherapy. So far as we know, there is no literature reported regarding how chronic stress could attenuate the anti-tumor immunity after radiotherapy from this perspective.

放射治疗是恶性肿瘤的重要治疗策略之一，然而以PD-1/PD-L1为代表的免疫抑制通路在很大程度上降低了放疗的疗效。肿瘤患者常处于慢性心理应激状态，致使体内以去甲肾上腺素（NE）为代表的压力相关激素水平升高。研究表明，β肾上腺素受体（β-AR）抑制剂可延长放疗的肿瘤患者的生存，然而机制不明。我们前期的研究发现，NE可通过激活β-AR上调乏氧诱导因子HIF-1α，促进其下游PD-1/PD-L1的表达。而PD-1/PD-L1通路的激活可抑制T细胞介导的特异性免疫应答。因此，我们推测，在慢性应激状态下，NE可通过β-AR---HIF-1α---PD-1/PD-L1通路促进放疗后免疫抑制；而β-AR拮抗剂可阻断这一过程，改善放疗后的抗肿瘤免疫反应。本项目拟模拟肿瘤患者所处的“慢性应激”状态构建荷瘤小鼠模型，探讨慢性应激对对放疗后肿瘤免疫微环境的影响及可能的的机制。据我们所知，目前国内外尚无类似报道。