# Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma

> **NIH CA R01** · NORTHWESTERN UNIVERSITY · 2026 · $496,357

## Abstract

Project Summary/Abstract
Glioblastoma, IDH-wildtype (GBM; WHO grade 4), the most malignant primary brain
tumor, has well-defined pre-necrotic, necrotic and recurrent growth phases. Transition to
the necrotic phase in primary and recurrent states involves a massive restructuring of
the tumor microenvironment (TME), in which there is a dramatic increase in tumor-
associated macrophages (TAMs) that are polarized to an immunosuppressive state.
TAMs emerge from the perivascular niche and aggregate in high density with hypoxic
glioma cells within the peri-necrotic niche (PN) with remarkable temporal similarity. We
hypothesize that the spatial arrangement of TAMs and glioma cells within the highly
hypoxic PN represents a biologic engine that serves as a sustainable source of TAM
immunosuppression and is reliant on their synergistic interdependencies. We propose
investigations to better understand mechanisms underlying these events using patient-
derived, molecularly characterized GBM neurosphere cultures and RCAS-tv-a mouse
model that allows study of the evolution of TME events following necrosis in real-time in
vivo and with advanced spatial transcriptomics. We focus on specific signaling events
within the PN that cause polarization of TAMs and have preliminary data indicating that
the hypoxic expression of podoplanin (PDPN) by glioma cells activates CLEC5A on
TAMs, causing an immunosuppressive phenotype through Syk/STAT3 signaling. We
also suggest that the direct effects of hypoxia and TGFβ1 activate Hippo signaling and
PDPN expression within this niche. Pharmacologic inhibition of Syk as a single agent
prolongs survival and enhances the presence of CD8+ T cells in the RCAS/tv-a model of
GBM. We hypothesize that therapeutic targeting of CLEC5A signaling by using Syk
inhibitors in addition to standard of care chemoradiation, with or without checkpoint
inhibitors, will diminish immunosuppression, enhance immunity and prolong survival in
preclinical models of primary and re

## Key facts

- **NIH application ID:** 11298343
- **Project number:** 1R01CA295560-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DANIEL J BRAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $496,357
- **Award type:** 1
- **Project period:** 2026-04-17T00:00:00 → 2031-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11298343

## Citation

> US National Institutes of Health, RePORTER application 11298343, Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma (1R01CA295560-01A1). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/11298343. Licensed CC0.

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