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; Hui Wang

doi:10.1038/s41467-021-25967-9

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

Nat Commun. 2021 Sep 30;12(1):5725. doi: 10.1038/s41467-021-25967-9.

Authors

Chaobao Liu^#^{1

2}, Yang Yang^#¹, Cheng Chen^#¹, Ling Li^#¹, Jingquan Li¹, Xiaonan Wang¹, Qiao Chu¹, Lin Qiu³, Qian Ba¹, Xiaoguang Li⁴, Hui Wang^{5

6}

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
² School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
³ CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁴ State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
⁵ State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
⁶ CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B7-H1 Antigen / antagonists & inhibitors
Carbon Tetrachloride / administration & dosage
Carbon Tetrachloride / toxicity
Chemokine CCL2 / antagonists & inhibitors
Chemokine CCL2 / metabolism
Diethylnitrosamine / administration & dosage
Diethylnitrosamine / toxicity
Drug Resistance, Neoplasm / immunology*
Hepatic Stellate Cells
Hepatocytes
Humans
Immune Checkpoint Inhibitors / pharmacology*
Immune Checkpoint Inhibitors / therapeutic use
Liver / drug effects
Liver / immunology
Liver / pathology
Liver Neoplasms, Experimental / chemically induced
Liver Neoplasms, Experimental / drug therapy*
Liver Neoplasms, Experimental / immunology
Liver Neoplasms, Experimental / pathology
Male
Mice
Neuroimmunomodulation*
Organoids
Receptors, Adrenergic, beta / metabolism
Receptors, CCR2 / antagonists & inhibitors
Receptors, CCR2 / metabolism
Signal Transduction / drug effects
Signal Transduction / immunology
Stress, Psychological / immunology*
Sympathetic Nervous System / immunology
Tumor Escape
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology

Substances

B7-H1 Antigen
Ccl2 protein, mouse
Ccr2 protein, mouse
Cd274 protein, mouse
Chemokine CCL2
Immune Checkpoint Inhibitors
Receptors, Adrenergic, beta
Receptors, CCR2
Diethylnitrosamine
Carbon Tetrachloride