# Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology

> **NIH NIH U01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $778,050

## Abstract

PROJECT SUMMARY / ABSTRACT
The goal of this project is to dissect the immune evasion mechanisms and enable immunotherapy for children
with high-risk Group 3 medulloblastoma (G3MB) via systems immunology approaches. Brain tumors are the
leading cause of cancer-related deaths in children. Medulloblastoma is the most prevalent malignant pediatric
brain tumor and is characterized by four major molecular subgroups, among which G3MB is the most aggressive
form and features MYC overexpression. The immunosuppressive tumor microenvironment (TME) is poorly
understood in G3MB, and no immunotherapy is available for children with this high-risk disease. Systems
immunology approaches—especially single-cell and spatial multi-omics profiling and in vivo CRISPR-based
functional screening—have proven powerful in dissecting tumor–TME interactions and identifying novel
immunotherapy targets in various cancer types, but very few studies have integrated these approaches. In our
preliminary studies, we applied two unique immunocompetent genetically-engineered mouse models (GEMMs)
of MYC-driven G3MB and performed scRNA-seq, scATAC-seq and spatial transcriptomics profiling. We enriched
immune cells from the TME by sorting CD45 positive cells for single-cell studies. Our preliminary analysis of
single-cell and spatial omics data revealed striking interactions of neural stem cell-like tumor cells with
macrophages and other immune cells that potentially create a suppressive TME and drive immune evasion in
mouse G3MB. We also performed in vivo CRISPR screening in tumor cells using the GEMMs to identify
modulators of tumor development, which demonstrated the feasibility of in vivo functional genomics screening
in our preclinical models. In this project, first, we propose to utilize cutting-edge single-cell and spatial omics
technologies to characterize the two G3MB GEMMs at different stages of tumor progression. We will use our
network-based tools to integrate these multi-omics data to dissect the dynamic tumor–immune interactions and
underlying “hidden” drivers that drive the immune exclusion and suppression during G3MB progression. We will
also validate discoveries of G3MB from mouse studies in patient samples. We will develop a cloud-based portal
to visualize and explore our single-cell and spatial data and tumor–TME interactomes of G3MB. Second, we will
establish the mechanistic basis of tumor–T cell interactions and strategies to enable adoptive T cell therapy for
G3MB by discovering functional drivers and putative targets in both tumor cells and T cells. To this end, we will
apply both candidate approach and in vivo CRISPR screening in immunocompetent GEMMs to identify tumor-
intrinsic modulators that will remodel the suppressive TME and sensitize G3MB tumors to adoptive T cell and
CAR-T cell therapies. We will also test if targeting inhibitory factors for T cell function will enable and optimize
effective adoptive T cell therapies against such tumors. Our studies promi...

## Key facts

- **NIH application ID:** 10924068
- **Project number:** 5U01CA281868-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Hongbo Chi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $778,050
- **Award type:** 5
- **Project period:** 2023-09-07 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10924068

## Citation

> US National Institutes of Health, RePORTER application 10924068, Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology (5U01CA281868-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10924068. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*