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Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

ABSTRACT: Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13+ fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE302373 | GEO | 2026/05/19

REPOSITORIES: GEO

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Project description:Low bone mass is strongly associated with multiple neurologic diseases such as Alzheimer’s disease (AD), however it remains unclear if this represents direct specific biologic sequalae of the primary disease process or rather a non-specific finding attributable to alterations in behavior and activity. The recent discovery of skeletal stem cells (SSCs) generating bone forming osteoblasts offers a new opportunity to understand both AD effects on bone and broader neural effects on bone by determining whether there are neural contributions to the SSC niche. Deletion of p75NTR (an essential neurotrophin receptor) was used to probe the contributions of peripheral innervation to the SSC niche. p75NTR deletion either broadly in neurons (p75NTRsyn1 mice) or more specifically in sensory nerves (p75NTRadv mice) but not osteogenic cells (p75NTRocn and p75NTRprx1 mice) or sympathetic nerves (p75NTRth mice), led to decrease in sensory innervation, impaired SSC homeostasis, and bone loss. Consistent with this, pharmacological sensory denervation resulted in a decrease in SSC numbers. More directly, wild-type SSCs transplanted orthotopically into the bones of p75NTRadv host mice with reduced sensory innervation displayed an impaired osteogenic capability, indicating that sensory nerves comprise part of the SSC niche. Decreased sensory innervation in p75NTRadv mice further impaired fracture healing by suppressing SSC expansion. Transcriptomic profiling to identify sensory nerve derived mediators of the SSC niche effect identified that p75NTR regulates expression of Osteopontin (SPP1) in neurons of the dorsal root ganglion (DRG), and SPP1 in turn acts as to promote SSC self-renewal and osteogenic capacity. Lastly, this p75NTR-SPP1 axis is impaired in AD mice, providing a new, direct mechanism for osteopenia in AD both impacting basal bone turnover and fracture repair. Altogether, our findings newly establish sensory nerves as a key component of SSC niche that is disrupted in AD, providing new therapeutic opportunities to augment SSC function to treat bone disorders such as Alzheimer’s associated osteopenia.

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Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

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