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Role of IRF2BP2 in Tumor Immune Evasion

Award Number: F31CA254259
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/18/2025

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Role of IRF2BP2 in Tumor Immune Evasion - PROJECT ABSTRACT Understanding the tumor microenvironment (TME) and the prognostic relevance of the cells contributing to it is vital for developing novel treatments for medulloblastoma (MB), the most common malignant pediatric brain tumor. Immune resistance in a murine model of MB (MM1) is associated with enhanced tumor expression of the immune checkpoint programmed death ligand-1 (PD-L1) in response to anti-tumor cytokine interferon-gamma (IFNγ) signaling. Disruption of this pathway via knockdown of cyclin dependent kinase 5 (CDK5), an essential transducer of the IFNγ signal, leads to an inflammatory TME phenotype and enhanced tumor rejection in vivo. IFNγ-induced PD-L1 gene expression is thought to be regulated at the promoter level by competition between the transcriptional activator IRF1 and repressor IRF2. IFNγ-Cdk5 signaling decreases IRF2 expression and is associated with hypo-phosphorylation of its co-repressor IRF2BP2, driving IRF1-mediated transcriptional activation. IRF2BP2 has emerged as a vital transcriptional co-factor in multiple cell types, with roles in the regulation of apoptosis, cell cycling, and inflammation. However, its function in cancer is poorly defined. We hypothesize that formation of the IRF2/IRF2BP2 co-repressor normally attenuates PD-L1 transcription, and that inhibition of this complex by IFNγ-Cdk5 signaling unleashes PD-L1 expression and results in immune evasion. This project aims to assess the function of the IRF2/IRF2BP2 complex at the PD-L1 promoter level during basal and IFNγ- stimulated conditions in MB, with complementary studies on how perturbations in this tumor-intrinsic signaling pathway leads to shifts in the TME composition in vivo. Aim 1 will characterize the role of IRF2BP2 in mediating the function of interferon-sensitive response elements (ISRE)-containing gene promoters. Aim 2 will assess the effect of IRF2BP2 on tumor growth and immune infiltration in vivo. Success in this effort will enable an in-depth understanding of the tumor-intrinsic regulation of immune sensitivities in MB, thereby facilitating rational targeted immunotherapeutic approach development in the future against MB and possibly other cancers.


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: 2026 ( Subtotal = -$987 )
2026	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	4	11/24/2025	NON-COMPETING CONTINUATION	-$987
														Subtotal = -$987

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	4	5/21/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	3	5/31/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	2	5/23/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	001	1	4/29/2021	NEW	$0
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	1	4/29/2021	NEW	$51,036
														Subtotal = $51,036

Grand Total All Awards = $208,469

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Role of IRF2BP2 in Tumor Immune Evasion

Award Number: F31CA254259

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/18/2025

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