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

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2024 · $77,098

## Abstract

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.

## Key facts

- **NIH application ID:** 10914934
- **Project number:** 5R01CA276284-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Hui Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,098
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914934

## Citation

> US National Institutes of Health, RePORTER application 10914934, Mechanism of double-negative T cells in antitumor immunity to breast cancer (5R01CA276284-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10914934. Licensed CC0.

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