Environmental eustress modulates β-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice

作者：Chaobao Liu, Yang Yang, Cheng Chen, Ling Li, Jingquan Li, Xiaonan Wang, Qiao Chu, Lin Qiu, Qian Ba, Xiaoguang Li, Hui Wang · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-25967-9 · 被引用次数：67 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Vagus Nerve Stimulation Research、Stress Responses and Cortisol

Abstract Although psycho-social stress is a well-known factor that contributes to the development of cancer, it remains largely unclear whether and how environmental eustress influences malignant diseases and regulates cancer-related therapeutic responses. Using an established eustress model, we demonstrate that mice living in an enriched environment (EE) are protected from carcinogen-induced liver neoplasia and transplantable syngeneic liver tumors, owning to a CD8 + T cell-dependent tumor control. We identify a peripheral Neuro-Endocrine-Immune pathway in eustress, including Sympathetic nervous system (SNS)/β-adrenergic receptors (β-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and β-ARs signaling in tumor cells and tumor infiltrated myeloid cells, leading to suppression of CCL2 expression and activation of anti-tumor immunity. Either blockade of CCL2/CCR2 or β-AR signaling in EE mice lose the tumor protection capability. Our study reveales that environmental eustress via EE stimulates anti-tumor immunity, resulting in more efficient tumor control and a better outcome of immunotherapy.