Decoding Dural Nociceptors as Drivers of Immune Suppression in Glioblastoma

Project Summary (Abstract):
Glioblastoma (GB) remains one of the most lethal cancers, characterized by a profoundly immunosuppressive
tumor microenvironment (TME) that limits the effectiveness of current immunotherapies. While research
has heavily focused on traditional regulators of immune cells, nociceptors—pain-sensing sensory neurons
known to regulate immune responses in the periphery—have not been studied in GB, creating a significant
gap in our understanding of immune regulation in the disease. Of note, in the cranial region, nociceptors
are densely concentrated in the dural layer of the meninges but are absent from the brain parenchyma.
This anatomical separation from GB tumors has likely contributed to their historical neglect in GB research,
overlooking their potential as critical regulators of anti-tumor immunity.
Our preliminary data provide compelling evidence that nociceptors play an active role in GB pathogenesis. In
syngeneic orthotopic GB mouse models, we observed heightened activation of dural nociceptors in the presence
of tumors, marked by increased production of calcitonin gene-related peptide (CGRP), a neuropeptide with
known immunomodulatory functions. Furthermore, cerebrospinal fluid (CSF) from GB-bearing mice promotes
pronounced axonal elongation in cultured primary trigeminal nociceptors, indicating that tumor-derived factors
can directly modulate these neurons. Strikingly, nociceptor ablation in GB-bearing mice leads to transformative
changes: prolonged survival, a shift in the TME from an immune-suppressive ‘cold’ state to an immune-activating
‘hot’ state and enhanced responsiveness to immune checkpoint blockade (ICB) therapy. These findings
demonstrate that nociceptors, despite their physical separation from the tumor, can remotely regulate GB
progression by modulating the immune landscape.
To elucidate the mechanisms underlying nociceptor-mediated immune regulation in GB, we are employing
methodologies including ELISAs, in vitro neuronal culture assays, single-nucleus and single-cell RNA
sequencing (snRNA-seq, scRNA-seq), multi-dimensional flow cytometry, and survival studies under
conditions of immune perturbation. These approaches will elucidate the tumor-derived factors that modulate
nociceptors and define the bidirectional interactions between nociceptors and immune cells within the TME,
revealing the mechanisms by which these neurons regulate anti-tumor immunity.
Beyond advancing fundamental understanding, this work holds significant therapeutic potential. By targeting
nociceptor-driven immune regulation, we aim to develop strategies to reverse immune suppression in GB,
including repurposing existing nociceptor-targeting therapies to enhance efficacy of immunotherapies. Ultimately,
our goal is to uncover new therapeutic avenues for improving survival outcomes in patients with this devastating
disease.

Grant Number: 1R21CA309473-01
NIH Institute/Center: NIH
Principal Investigator: Nandini Acharya