NIH grant: Immunotherapy for Glioblastoma by Targeting an Immunoregulatory Neuropeptide (1R01CA304655-01A1)

retained text

NIH grant 1R01CA304655-01A1: Immunotherapy for Glioblastoma by Targeting an Immunoregulatory Neuropeptide
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Nandini  Acharya. Award: $567754.
Start: 2026-06-23T00:00:00.
lioblastoma (GBM) is the most lethal primary brain tumor, marked by limited treatment options and poor
survival. GBM is also remarkably resistant to immunotherapy due to CD8⁺ T cell exclusion and dysfunction,
largely driven by immunosuppressive myeloid cells—particularly tumor-associated macrophages (TAMs). This
positions TAMs as central targets for rewiring anti-tumor immunity. Our studies uncover a previously
unrecognized tumor–host interaction: GBM activates trigeminal sensory neurons—specifically, meningeal
nociceptors—which in turn release elevated levels of the immunoregulatory neuropeptide calcitonin gene–
related peptide (CGRP). CGRP acts via its receptor, receptor activity–modifying protein 1 (RAMP1), to reprogram
TAMs toward an immunosuppressive phenotype. In syngeneic orthotopic murine GBM models, nociceptor
ablation significantly prolongs survival and, importantly, sensitizes previously unresponsive GBM to immune
checkpoint blockade (ICB). It enhances antitumor immunity by reducing TAM-mediated suppression, boosting
CD8⁺ T cell infiltration and function, and limiting T cell exhaustion—a hypofunctional state characterized by
impaired cytokine production, reduced cytotoxicity, and sustained expression of inhibitory receptors. Strikingly,
GBM-bearing mice with myeloid-specific RAMP1 deletion phenocopy these effects. Furthermore, the survival
benefit is lost upon CD8⁺ T cell depletion, underscoring a critical CGRP-driven TAM–T cell axis in immune
escape. At the molecular level, we uncover a mutually antagonistic interaction between CGRP and interferongamma (IFN-γ), a key pro-inflammatory cytokine essential for anti-tumor immunity. CGRP suppresses IFN-γ–
STAT1 signaling in TAMs, while IFN-γ inhibits CGRP-induced cAMP signaling and RAMP1 expression—
establishing a reciprocal regulatory loop that governs TAM polarization. Of note, while TAMs are known drivers
of immune suppression in GBM, the upstream signals that program their identity remain largely unclear. We
identify a neuroimmune axis in which nociceptor-derived CGRP reprograms TAMs to drive CD8⁺ T cell
exhaustion in the GBM TME. However, how CGRP reprograms TAMs at the molecular level—and how this
drives T cell exhaustion—remains unresolved. Addressing this will define a new mechanism of immune
suppression in GBM and reveal actionable neuroimmune targets to overcome immunotherapy resistance. In this
proposal, we will define how CGRP–RAMP1 signaling enforces TAM-mediated immune suppression by
dampening TAM sensitivity to IFN-γ. We will dissect the transcriptional and epigenetic programs underlying this
crosstalk using single-cell multiomic profiling, and leverage spatial transcriptomics and advanced imaging to map
how RAMP1⁺ TAMs promote CD8⁺ T cell exhaustion within the GBM TME. Because these studies aim to resolve
integrated neuroimmune interactions that require intact tumor architecture, immune competence, and neuronal
circuitry, we will employ immunocompetent, syngeneic orthotopic murine GBM models, which are essential to
faithfully recapitulate these processes in vivo and cannot be modeled in vitro. By identifying the CGRP–RAMP1
axis as a targetable neuroimmune checkpoint, this work reveals a previously uncharacterized driver of immune
evasion in GBM and opens the door to repurposing FDA-approved drugs targeting trigeminal sensory neurons
and their downstream signaling pathways to overcome immunotherapy resistance in this intractable cancer

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