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Tumor Intrinsic Regulation of Immune Evasion Pathways in Breast Cancer

Award Number: K00CA245552
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/12/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Tumor Intrinsic Regulation of Immune Evasion Pathways in Breast Cancer - Project Summary/Abstract: The incidence rate of cutaneous melanoma has doubled since 1973, and is increasing more rapidly than any other cancer. FDA-approved targeted inhibitors and immune checkpoint therapies have high response rates in melanoma; however, both innate and acquired resistance remain significant issues. Strategies that combine targeted and immune therapy show promise; however, a comprehensive understanding of the crosstalk between cancer cells and immune cells is lacking. Our central hypothesis is that tumor intrinsic signaling modulates the anti-tumor immune response, and elucidation of pathways that drive these interactions can lead to novel therapeutic strategies. Through the successful completion of the following two aims, we will gain insight into tumor intrinsic signaling pathways that regulate anti-tumor immunity. In the F99 phase, we are investigating a novel regulation of the understudied immune checkpoint protein VISTA. VISTA is an inhibitory immune checkpoint primarily expressed on hematopoietic cells. In a novel finding, we observed that VISTA is expressed on melanoma cells in patient samples and in cell lines. Its tumor-specific expression promoted tumor initiation in vivo, associated with an increase in Foxp3+ CD4+ T regulatory cells (Tregs). We demonstrated that BRAF inhibitor (BRAFi) treatment reduced VISTA expression, and BRAFi-induced upregulation of FOXD3 negatively regulated VISTA transcript levels. BRAF/MEK inhibitors are used clinically, which motivates us to further investigate the role of VISTA, a BRAF-FOXD3-regulated immune checkpoint protein, in modulating immune responses. In the first aim, we will test the hypothesis that tumor-expressed VISTA promotes Treg induction and enhances Treg suppressive function. Tregs can limit the efficacy of immunotherapy; thus, we will also test the hypothesis that tumor-specific expression of VISTA alters the response to PD-1 blockade. In the K00 phase, we will broadly investigate cancer cell signaling pathways that allow cells to evade immune detection during metastasis. Tumor cells employ various mechanisms to depart from the primary tumor site and colonize new organs. We hypothesize that tumor intrinsic signaling pathways play a critical role in immune evasion during metastasis. In aim 2, we will use a CRISPR/Cas9 screen in a spontaneous metastasis model to identify genes that promote metastasis. We will compare results between immune competent and immune compromised models to determine genes that specifically promote metastasis when under pressure from the immune system. Completion of these studies will bring valuable insights into the complex interactions between tumor and immune cells. The training provided in both of these phases will build a solid foundation in cancer biology, tumor immunology, and metastasis, contributing towards the long-term goal of conducting research on tumor immunology as an academic principal investigator.


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: 2024 ( Subtotal = $181,475 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Cause and Prevention Research	001	6	9/3/2024	NON-COMPETING CONTINUATION	$82,579
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Cause and Prevention Research	000	6	4/30/2024	NON-COMPETING CONTINUATION	$98,896
														Subtotal = $181,475

Issue Date FY: 2023 ( Subtotal = $94,380 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Cause and Prevention Research	000	5	4/25/2023	NON-COMPETING CONTINUATION	$94,380
														Subtotal = $94,380

Issue Date FY: 2022 ( Subtotal = $89,864 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Cause and Prevention Research	000	4	4/26/2022	NON-COMPETING CONTINUATION	$89,864
														Subtotal = $89,864

Issue Date FY: 2021 ( Subtotal = $86,968 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Cancer Cause and Prevention Research	000	3	5/12/2021	EXTENSION WITH OR WITHOUT FUNDS	$86,968
														Subtotal = $86,968

Grand Total All Awards = $452,687

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Tumor Intrinsic Regulation of Immune Evasion Pathways in Breast Cancer

Award Number: K00CA245552

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/12/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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