# Mechanism of double-negative T cells in antitumor immunity to breast cancer > **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2024 · $258,021 ## 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 (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), breast cancer can be classified into three major subtypes: luminal subtype (ER/PR+, HER2-), HER2+ subtype (ERa/HR-, HER2+), and triple-negative subtype (TNBC, ERa/HR-, HER2-). Luminal, HER2+, and TN subtype makes up 70%, 15-20%, and 15% of BC, respectively. BC is metastatic disease. Typical systemic therapies for metastatic BC are endocrine therapy for luminal BC, chemotherapy plus HER2- target therapy for HER2+ BC, and chemotherapy for TNBC. The median overall survival for metastatic BC is 4- 5 years for luminal BC, 5 years for HER2+ BC, 1 year for TNBC. Once chemoresistance develops, metastatic BC is incurable. Cancer immunotherapy has achieved unprecedented success in treating many advanced cancers, including TNBC. However, the response rate of BC patients to cancer immunotherapy is very low because of the poor tumor infiltration of tumor-infiltrating lymphocytes (TIL). Developing more effective cancer immunotherapy approaches is critical to treating and curing metastatic BC 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 BC development and growth. We further found that the cell transfer-induced antitumor immunity was mediated by tissue-resident CD4-CD8- double-negative T (DN T) cells and depended on NK cells. Deciphering the underlying mechanism will allow us to develop a powerful immunotherapy approach for BC 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 cells in antitumor immunity to breast cancer. Our central hypothesis is that the Ja281 KO mice lack a population of immunoregulatory T cells, which allow the transferred DN T cells to form antitumoral tissue-resident cells to inhibit EO771 tumor development and growth by eradicating tumor cells. We will test this hypothesis by pursuing the following three specific aims: Aim 1: Determine the formation and characterization of tissue- resident DN T cells from the transferred DN T cells in the Ja281 KO mice. Aim 2. Determine the antitumor function of tissue-resident DN T/NK cell axis. Aim 3: Determine the cells governing tissue-resident DN T cell formation and antitumor function. The finding that tissue-resident DN T cells can inhibit EO771 tumor formation and 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 BC immunotherapy. ## Key facts - **NIH application ID:** 11329371 - **Project number:** 7R01CA276284-03 - **Recipient organization:** UNIVERSITY OF LOUISVILLE - **Principal Investigator:** Hui Zhang - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $258,021 - **Award type:** 7 - **Project period:** 2023-09-01 → 2028-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11329371 ## Citation > US National Institutes of Health, RePORTER application 11329371, Mechanism of double-negative T cells in antitumor immunity to breast cancer (7R01CA276284-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11329371. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*