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Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells

Award Number: R01CA259001
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/19/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells - Project Summary/Abstract Breast tumors are rarely eradicated by chemotherapy. Residual disease exists for 2 reasons: the tumor cells 1) avoid death from apoptosis, mitotic catastrophe, and nutrient deprivation; 2) avoid immune clearance. Our previous research has established that by activating p53-mediated programs of arrest and senescence, tumor cells avoid death by mitotic catastrophe, apoptosis, and nutrient deprivation. We showed chemotherapy treated breast cancer patients with p53 wild type tumors have dismal survival compared to patients with p53 mutant tumors. Senescent cells promote relapse by their production of cytokines and chemokines (termed the senescence associated secretory phenotype, or SASP). The weakness of prior research has been a failure to identify how the treated, senescent tumor cells avoid immune clearance. In this proposal, we present compelling preliminary data addressing this weakness, and plans to fully characterize and investigate potential therapeutic avenues that target the evasion of cell death, thus facilitating immune clearance and improving survival. In preliminary data, we identify a remarkable upregulation of PD-L1 in the persisting residual disease likely mediated through interactions with stromal cells, and expression is maintained in the relapse, suggesting a strong selective pressure. The goal of this project is to identify mechanisms and develop strategies to target immune evasion specifically in tumor cells that have survived chemotherapy by entering senescence. Hypothesis: Stromal interferon gamma (IFNγ) induces PD-L1 in a specific subset of cells in a chemotherapy- treated, senescent tumor. These persisting, senescent tumor cells can be targeted using a novel strategy that combines senolytic drugs to induce immunogenic cell death followed by immune checkpoint inhibitors. In Aim 1 we will use mouse mammary tumor models to determine if PD-L1 expressing tumor cells have greater relapse potential than cells within the same treated tumor that do not express PD-L1, and how each responds to retreatment. We will characterize gene expression differences in cells that express PD-L1 vs. those that do not. In Aim 2 we will identify the factors in vivo that are required for PD-L1 upregulation on senescent tumor cells. We will transplant mammary tumors into syngeneic mice that lack specific immune components such as T cells, treat with chemotherapy, and determine changes in PD-L1 expression and immune contexture. In Aim 3, preliminary data show only one third of senescent mouse mammary tumors responded to anti-PD-L1 therapy following chemotherapy. We will test if inducing immunogenic cell death with BH3 mimetic drugs we have shown to have senolytic activity can improve the response to immune checkpoint inhibitors. In Aim 4, we will use multiplex immunohistochemistry staining of human breast cancer specimens pre and post chemotherapy to determine if PD-L1 expression is induced in senescent tumors.


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 = $417,650 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	000	4	2/13/2025	NON-COMPETING CONTINUATION	$375,885
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	001	4	6/4/2025	NON-COMPETING CONTINUATION	$41,765
														Subtotal = $417,650

Issue Date FY: 2024 ( Subtotal = $410,550 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	001	3	4/15/2024	NON-COMPETING CONTINUATION	$21,607
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	000	3	2/5/2024	NON-COMPETING CONTINUATION	$388,943
														Subtotal = $410,550

Issue Date FY: 2023 ( Subtotal = $419,189 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	000	2	2/3/2023	NON-COMPETING CONTINUATION	$419,189
														Subtotal = $419,189

Issue Date FY: 2022 ( Subtotal = $432,347 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	001	1	4/21/2022	NEW	$0
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cancer Biology Research	000	1	4/19/2022	NEW	$432,347
														Subtotal = $432,347

Grand Total All Awards = $1,679,736

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Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells

Award Number: R01CA259001

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/19/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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