# Developing a novel combination immunotherapy for triple-negative breast cancer

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2024 · $618,212

## Abstract

PROJECT SUMMARY
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a very poor
prognosis due to its tendency to metastasize and relapse. Immune checkpoint blockade (immunotherapy) plus
chemotherapy is the first-line treatment for metastatic TNBC, but the tumor responses are limited and not
durable. Additionally, the lack of robust predictive biomarkers of response remains a limiting factor in
maximizing the efficacy of immunotherapy. Therefore, there is an urgent need to develop a more effective
immunotherapy combination and establish novel biomarkers to identify TNBC patients who will benefit from
this treatment. Because the tumor microenvironment (TME) critically influences TNBC response to
immunotherapy, we set out to identify mechanisms that broadly mediate the immune response in TNBC. Our
preliminary studies showed that the c-Jun N-terminal kinase (JNK) pathway acts as a TME master switch in
promoting a persistent immunosuppressive TME in TNBC. Building on this evidence, our central hypothesis is
that JNK inhibitors (JNKi) synergize with immunotherapy by converting the TNBC TME from an
immunosuppressive to an immunoactive state. Our hypothesis will be tested through 3 specific aims: Aim 1)
Determine how JNK regulates the immunosuppressive TME and aggressiveness in TNBC; Aim 2) Establish
JNK signaling-related biomarkers of the immunosuppressive status of the TNBC TME; and Aim 3) Develop an
optimal JNKi-immunotherapy combination for TNBC. Completing these aims will provide a robust scientific
framework for developing effective therapeutic strategies for TNBC. The experimental approach will be as
follows: In Aim 1, we will investigate how JNK promotes TNBC aggressiveness by immunologically modulating
the TME using clinically relevant immunocompetent syngeneic TNBC mouse models with well-defined immune
TMEs. We will also identify molecules responsible for JNK’s immunological modulation of the TME. In Aim 2,
we will establish novel JNK signaling-related biomarkers reflecting the immunosuppressive status of the TNBC
TME using patient samples. In Aim 3, we will test whether JNKi synergize with immunotherapy in TNBC by
promoting an immunoactive TME, using clinically relevant immunocompetent syngeneic TNBC mouse models
and our established patient-derived xenografts of TNBC molecular subtypes (sensitive or resistant to
immunotherapy) in humanized mouse models. We expect to 1) generate sufficient preclinical data to support
the development of an effective JNKi-immunotherapy combination for patients with TNBC and 2) establish
biomarkers of the immunosuppressive status of the TNBC TME. The proposed research is significant because
it will fundamentally advance our understanding of mechanisms by which cancers promote suppression of the
response to immunotherapy and may lead to the development of a novel combination immunotherapy that
improves the survival of TNBC patients.

## Key facts

- **NIH application ID:** 10930903
- **Project number:** 5R01CA278056-02
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Naoto T. Ueno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $618,212
- **Award type:** 5
- **Project period:** 2023-09-18 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930903

## Citation

> US National Institutes of Health, RePORTER application 10930903, Developing a novel combination immunotherapy for triple-negative breast cancer (5R01CA278056-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930903. Licensed CC0.

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