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

Award Number: U01CA281868
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology - 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 promise to provide new insights into mechanisms of tumor–TME interactions in G3MB and manifest legitimate immunotherapeutic opportunities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $819,000 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	7/28/2025	NON-COMPETING CONTINUATION	$819,000
														Subtotal = $819,000

Issue Date FY: 2024 ( Subtotal = $778,050 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	8/6/2024	NON-COMPETING CONTINUATION	$778,050
														Subtotal = $778,050

Issue Date FY: 2023 ( Subtotal = $819,000 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/7/2023	NEW	$819,000
														Subtotal = $819,000

Grand Total All Awards = $2,416,050

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

Award Number: U01CA281868

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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