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

Chaobao Liu, Yang Yang, Cheng Chen, Ling Li, Jingquan Li, Xiaonan Wang, Qiao Chu, Lin Qiu, Qian Ba, Xiaoguang Li () and Hui Wang ()
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Chaobao Liu: Shanghai Jiao Tong University School of Medicine
Yang Yang: Shanghai Jiao Tong University School of Medicine
Cheng Chen: Shanghai Jiao Tong University School of Medicine
Ling Li: Shanghai Jiao Tong University School of Medicine
Jingquan Li: Shanghai Jiao Tong University School of Medicine
Xiaonan Wang: Shanghai Jiao Tong University School of Medicine
Qiao Chu: Shanghai Jiao Tong University School of Medicine
Lin Qiu: Chinese Academy of Sciences
Qian Ba: Shanghai Jiao Tong University School of Medicine
Xiaoguang Li: Shanghai Jiao Tong University School of Medicine
Hui Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25967-9

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