Abstract 372P
Background
The nervous system’s role in tumor progression has been recognized, but mechanisms of neural modulation in lung tumor microenvironment are elusive.
Methods
Immunotherapy effectiveness in 98 EGFR-negative Non-small Cell Lung Cancer (NSCLC) patients using β-blockers was analyzed. Tumor sympathetic innervation was mapped using whole-tissue immunolabeling and 3D imaging in 20 NSCLC, 7 metastatic lung tumors (breast/colorectal origin), and 5 benign samples, alongside C57BL/6 orthotopic Lewis lung carcinoma and MMTV-PyMT +/− mouse models. Sympathetic ablation was achieved via intranasal 6-Hydroxydopamine and sympathectomy. Single-cell RNA sequencing (scRNA-seq) identified immunosuppressive neutrophil subtypes, and neutrophil-specific β2-adrenergic receptor (Adrb2) signal was blocked using Ly6g-Cre;Adrb2fl/fl mice and pharmacological inhibition.
Results
Firstly, we noted β-blocker administration significantly improved immunotherapy outcomes in NSCLC patients, evidenced by higher complete or partial response rates, highlighting the therapeutic benefits of sympathetic signal inhibition. Then, using 3D imaging techniques, abundant sympathetic innervations were detected within primary and metastatic lung tumors and proved to project inside them in both human and mouse models, but were absent in benign samples. Ablation of local sympathetic inputs in mice, either chemically or surgically, suppressed lung tumor progression and increased CD8+ T cell infiltration, demonstrating sympathetic pathways regulating tumor growth and immunity. To explore molecular mechanism, scRNA-seq revealed immunosuppressive neutrophils with elevated Cd274 expression andmyeloid recruitment factors, uniquely enriched in both primary and metastatic lung tumors. Sympathetic Adrb2 signaling enhanced the immunosuppressive gene expression and tumor-promoting activity of these neutrophils. Targeted inhibition of Adrb2 reduced CD274+ neutrophils, diminished tumor progression, and prolonged survival in primary and metastatic mouse models, confirming their role.
Conclusions
This study first revealed that sympathetic nerves promote lung tumor progression through immunosuppressive neutrophils in the microenvironment.
Legal entity responsible for the study
J. Yang
Funding
This work has been supported by the National Key Research and Development Program of China (#2023YFA1801901 to J.Y.; #2022YFA1103900 to J.C.), the National Natural Science Foundation of China (#32125017 and #32150008 to J.Y.; #82388102 and #92259303 to K.C.; #82173386 to M.Q.), the Beijing Natural Science Foundation (#Z240013 and #L234002 to K.C.; #7232086 to J.Y; #7234378 to Y.C; #QY23070 to R.J.), the Chinese Academy of Medical Sciences (#2021RU002 and #2022-I2M-C&T-B-120 to K.C.; #2019-I2M-5-015 to J.C.), and Peking University People’s Hospital Scientific Research Development Funds (#RZG2024-02 to K.C.; #RZ2022-04 to M.Q.).
Disclosure
All authors have declared no conflicts of interest.