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FOXM1-Mediated Regulation of Anti-Tumor Immune Memory and Its Potential as a Target for Therapeutic Vaccination in Triple-Negative Breast Cancer

Award Number: F30CA310537
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/27/2027
PERIOD OF PERFORMANCE END DATE: 02/26/2028

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FOXM1-Mediated Regulation of Anti-Tumor Immune Memory and Its Potential as a Target for Therapeutic Vaccination in Triple-Negative Breast Cancer - Abstract Immunotherapy response in patients with most solid cancers including triple negative breast cancers (TNBCs) is not optimal. TNBCs are particularly challenging due to their aggressive nature, lack of targeted therapies, and traits such as high genomic instability and increased tumor mutation burden (TMB), which theoretically should improve immunotherapy responsiveness. Despite these factors, the majority of TNBC patients do not respond to immunotherapy, likely due to multiple defects in the anti-tumor immunity cascade. A better understanding of the factors/mechanisms that promote immunosuppression in the tumor microenvironment or prevent response to immunotherapy will pave the way for development of targeted therapeutics. In this application, we present compelling evidence suggesting FOXM1 as a key tumor intrinsic factor that contributes to these challenges. Using orthotopic mouse models, we showed that FOXM1 and its associated signaling inhibits the anti-tumor immunity in TNBCs. Our results reveal that depletion of tumor intrinsic FOXM1 promotes infiltration of T-cell, NK cells and myeloid cells, while blocking regulatory T cells (Treg) and myeloid suppressor cell function. Furthermore, using CD8+ T cell depletion mouse model, we demonstrate that activation of cytotoxic T cells is largely responsible for suppressing the tumor growth in FOXM1 depleted tumors. Our results demonstrate that FOXM1 suppresses stress ligands by epigenetically silencing DNA sensing protein STING, which involves FOXM1 recruiting DNMT1-UHRF1 epigenetic repressor complex to STING promoter. Additionally, we show that FOXM1 may inhibit MHCI-dependent antigen presentation. Importantly, our findings indicate that depleting FOXM1 facilitates the development of immune cell memory. Mice with FOXM1-depleted tumors showed no tumor growth upon rechallenge with wild-type TNBC cells, suggesting the development of robust and enduring T-cell memory that potentially offers significant protection against cancer recurrence. These findings led us to hypothesize that (a) FOXM1 promotes TNBC growth, progression and relapse by blocking anti-tumor immune memory and (b) targeting FOXM1 stimulates MHC-I presentation of a pool of immunogenic peptides and the expansion of memory T cells that block tumor relapse and therefore serves as a promising therapeutic vaccine strategy for cancer in general and TNBCs in particular. We will test these hypotheses with two specific Aims. In Aim 1, we will test how depletion of FOXM1 induces immune memory to promote long-term tumor growth suppression and prevent recurrence of TNBCs through the restoration of antigen presentation. In Aim 2, we will test whether targeting FOXM1 may serve as a promising strategy to identify and evaluate novel immunogenic peptides as bonafide candidates for therapeutic vaccine. We will employ an immunopeptidomics approach to discover novel peptides from FOXM1-depleted TNBC cells. We will further test the immunogenicity of these peptides using dendritic cell-based pulsing in vaccinated humanized models. Successful completion of this proposal will identify specific immunogenic peptides as vaccine candidates for treating TNBCs.


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 = $55,114 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Research Manpower	000	1	8/27/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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FOXM1-Mediated Regulation of Anti-Tumor Immune Memory and Its Potential as a Target for Therapeutic Vaccination in Triple-Negative Breast Cancer

Award Number: F30CA310537

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/27/2027

PERIOD OF PERFORMANCE END DATE: 02/26/2028

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