# The role of Myeloid cells in pediatric-high grade gliomas

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $651,334

## Abstract

Abstract: MPI R01- Hambardzumyan and Becher
Pediatric high-grade gliomas (pHGG) account for the most cancer-related deaths in children and have a median
survival of 12-15 months. One promising avenue of research is developing novel therapies targeting the
properties of non-neoplastic cell types within the tumor, such as myeloid cells, including tumor-associated
macrophages (TAMs) and neutrophils. Much is known about TAMs in adult high-grade gliomas. However, very
little is known about TAMs and neutrophils in pHGGs. pHGGs more commonly arise in infratentorial locations
like the brainstem, beyond the cerebral hemispheres as seen in adults. pHGGs also harbor distinct histone
mutations not found in adults. This raises the question of whether pHGGs possess a distinct constituency of
TAMs due to their unique genetic landscapes and locations.
Using human pHGG tissue samples and NanoString RNA sequencing, we demonstrate brainstem/midline
pHGGs (DMG) and murine diffuse intrinsic pontine glioma (DIPG) possess higher inflammatory scores and
increased neutrophil scores compared to hemispheric pHGGs, which are associated with shorter patient survival.
When examining only human hemispheric pHGGs, our results revealed two patient subsets with high and low
inflammatory scores. Patients with a high inflammatory score had significantly shorter survival times compared
to those with low inflammatory scores. We also show that human pHGGs possess high infiltration of IBA1+
TAMs, which are the most abundant non-neoplastic component of the pHGG tumor microenvironment (TME).
Our preliminary data utilizing mouse models to recapitulate pHGG in newborn immunocompetent mice combined
with various histone mutations in biologically relevant locations demonstrate murine tumors are strikingly similar
to their human counterparts with regard to their inflammatory immune profile and myeloid cell infiltration. Using
PDGFB and PDGFA as driver mutations to generate hemispheric pHGG in mice, we were able to recapitulate
human pHGGs with high and low inflammatory scores. We showed that in comparison to PDGFA-driven tumors,
PDGFB tumors have a higher inflammatory score, increased infiltration of monocytes from the blood, and shorter
survival time of tumor-bearing mice. We identify CCL3 as a potential key chemokine for CCR1/CCR5-positive
monocytes and CXCL1 for CXCR2-positive neutrophil recruitment in pHGG. Together, these results provide
strong rationale to extend our studies to understand how specific histone mutations and tumor locations influence
myeloid cell infiltration and how these cells promote pHGG growth. The outcome of these studies will: (i) reveal
the molecular and functional diversity of the myeloid compartment of pHGG; (ii) determine how distinct myeloid
subsets and myeloid-specific genes influence tumor growth and the TME; (iii) provide insight into how myeloid
subsets influence, and are affected by driver mutations, pediatric-specific histone mutations, and tumor location...

## Key facts

- **NIH application ID:** 10888981
- **Project number:** 5R01CA258636-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Oren Josh Becher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $651,334
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888981

## Citation

> US National Institutes of Health, RePORTER application 10888981, The role of Myeloid cells in pediatric-high grade gliomas (5R01CA258636-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10888981. Licensed CC0.

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