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A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

ABSTRACT: Body-brain communication has emerged as a key regulator of tissue homeostasis. Solid tumours are innervated by different branches of the peripheral nervous system, and increased tumour innervation is associated with poor cancer outcomes. However, it remains unexplored how the brain senses and responds to tumours in peripheral organs, and how tumour-brain communication influences cancer immunity. Here, we identify a previously unrecognized tumour-brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment (TME). Combining genetically engineered mouse models with neural tracing, calcium imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces increased innervation, activation and transcriptional alterations in vagal sensory neurons (VSNs), a major interoceptive system connecting visceral organs to the brain. Mechanistically, Npy2r+ vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the TME. This, in turn, suppresses anti-tumour immunity via β2-adrenergic signaling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer. Collectively, these results reveal a bidirectional tumour-brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour-brain circuit may provide new treatments for visceral organ cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE275770 | GEO | 2025/12/04

REPOSITORIES: GEO

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T cells and adipocyte IL-17RC control fat innervation and thermogenesis

Project description:The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation1,2. The molecular basis of this bi-directional communication is unknown. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGF1 in parenchymal cells via the IL-17 receptor complex (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGF1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGF1 expression. Ablating cells and the IL-17RC signalling pathway also impairs sympathetic innervation in salivary glands and the lungs. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation.

2020-03-02 | PXD017424 | Pride

Organ-specific Sympathetic Innervation Defines Visceral Functions

Project description:Organ-specific Sympathetic Innervation Defines Visceral Functions

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2008-01-31 | E-JJRD-1 | biostudies-arrayexpress

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Microbes modulate sympathetic neurons via a gut-brain circuit

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2020-03-20 | GSE145986 | GEO

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