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bioRxiv · 10.64898/2026.06.19.733335

The Neuro-Immune Axis in Glioma Spontaneous Remission: Evidence from Population-Level Latent Variable Modelling and Transcriptomic Profiling

Kapoor, A.·Tiwari, A.·Srivastava, S.
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Abstract

Gliomas are primary brain tumours that develop from neural stem or progenitor cells containing oncogenic alterations. Gliomas undergo remission with partial or complete disappearance of the disease, and in rare instances, spontaneous remission. Spontaneous remission happens without treatment or with inadequate medical intervention. This is a rare but well-documented phenomenon and has been observed across various tumour types, including gliomas, with varying frequency. While historically viewed as clinical anomalies, we hypothesize that SR may be driven by a measurable, latent neuro-immune axis specifically, autonomic vagal nerve modulation of the tumour microenvironment (TME) via the cholinergic anti-inflammatory pathway. Using a Gamma frailty Cox proportional hazards model on a SEER cohort of 6,939 glioma patients, we identified a latent biological variable (Z) that explains 27.1% of survival variance independent of age, grade, treatment, and tumour location. To determine the molecular basis of this latent survival advantage, we applied parallel frailty and Cox models to the TCGA Lower Grade Glioma and Glioblastoma (LGG+GBM) cohorts. Clinical validation confirmed expected hazards for age and grade, with the frailty model achieving high predictive accuracy (5-year AUC = 0.840; 10-year AUC = 0.841). Transcriptomic integration revealed that the alpha7 nicotinic acetylcholine receptor (CHRNA7) is highly protective, inversely correlating with biological frailty (r = -0.285, p < 0.0001). Conversely, pro-inflammatory cytokines (IL6) and M2 macrophage markers (CD163) positively correlated with frailty. Grade-stratified Cox regression and Kaplan-Meier analyses confirmed that CHRNA7 confers a significant survival advantage entirely independent of tumour grade. Single-cell RNA-sequencing data (Core GBmap) confirmed that CHRNA7 and TLR4 are expressed heavily on tumour-associated macrophages and microglia, rather than malignant cells. Our in-silico integration suggests that high vagal tone releases acetylcholine, binding to alpha7nAChR on TME macrophages. This triggers a signalling cascade that dampens the IL-6 production required for glioma proliferation, effectively halting tumour growth. Ongoing in vitro wet-lab experiments utilizing specific alpha7nAChR agonists (GTS-21) and physiological stress models aim to clinically validate this vagal-immune mechanism.

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Kapoor, A., Tiwari, A., Srivastava, S.. 2026-06-24. The Neuro-Immune Axis in Glioma Spontaneous Remission: Evidence from Population-Level Latent Variable Modelling and Transcriptomic Profiling. https://doi.org/10.64898/2026.06.19.733335

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