Tuesday, September 16, 2025 9/16/2025

Mechanism of double-negative T cells in antitumor immunity to breast cancer

Award Number: R01CA276284
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mechanism of double-negative T cells in antitumor immunity to breast cancer - Abstract: Breast cancer (BC), the most common cancer globally as of 2021 and accounting for 12% of all new annual cancer cases worldwide, is the most commonly diagnosed cancer among American women. Based on the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), breast cancer can be classified into three major subtypes: luminal subtype (ERa/PR+, HER2-), HER2+ subtype (ERa/HR-, HER2+), and triple-negative subtype (TNBC, ERa/HR-, HER2-). All types of BC have metastatic potential. TNBC is the deadliest form. Chemoresistance is a major obstacle to therapeutic efficacy. Once chemoresistance develops, metastatic BC is incurable. Cancer immunotherapy has achieved unprecedented success in treating many types of advanced cancers, including TNBC. However, the response rate of BC patients to cancer immunotherapy is low because of the poor tumor infiltration of tumor-infiltrating lymphocytes (TIL). Developing more effective cancer immunotherapy approaches is critical to treating and curing TNBC patients. Using a T cell receptor (TCR)-alpha deficient Ja281 KO mouse model, we found that transferring thymocytes into Ja281 KO mice could completely inhibit EO771 and Py8119 TNBC growth in these cell- transferred mice. We further found that the cell transfer-induced antitumor immunity was mediated by tissue- resident αβ+CD4-CD8- double-negative T (DN T) cells formed from the transplanted donor population and depended on host NK cells. Deciphering the underlying mechanism will allow us to develop a powerful immunotherapy approach for TNBC treatment. The long-term goal of our research is to develop new immunotherapeutic regimens for cancer treatment. The objective of this project is to decode the mechanism of DN T cell antitumor immunity to TNBC. Our central hypothesis is that DN T cells initiate antitumor immunity and interact with NK cells to control TNBC growth and to shape tumor microenvironment (TME) and that a population of immunoinhibitory T cells modulate DN T cell antitumor function. We will test this hypothesis by pursuing the following three specific aims: Aim 1: Determine how tissue-resident DN T cells are generated and how they mediate antitumor immunity using the Ja281 KO mouse model. Aim 2. Determine the antitumor function of tissue-resident DN T/NK cell axis. Aim 3: Define the immunoregulatory cells that govern tissue-resident DN T cell generation and their antitumor function. The finding that tissue-resident DN T cells can inhibit TNBC growth and eradicate breast cancer is novel. The completion of the proposed research will not only greatly advance our knowledge of DN T cells in antitumor immunity, but also allow us to develop more effective approaches for TNBC immunotherapy.


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 = $352,757 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Biology Research	002	4	9/5/2025	NON-COMPETING CONTINUATION	$352,757
2025	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Biology Research	001	3	8/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$258,021
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	2	8/22/2025	NON-COMPETING CONTINUATION	-$258,021
														Subtotal = $352,757

Issue Date FY: 2024 ( Subtotal = $335,119 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	2	8/5/2024	NON-COMPETING CONTINUATION	$335,119
														Subtotal = $335,119

Issue Date FY: 2023 ( Subtotal = $364,880 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	1	8/28/2023	NEW	$364,880
														Subtotal = $364,880

Grand Total All Awards = $1,052,756

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Mechanism of double-negative T cells in antitumor immunity to breast cancer

Award Number: R01CA276284

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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