# Harnessing neutrophils to improve the efficacy of immune checkpoint inhibitors in breast cancer

> **NIH NIH K99** · BAYLOR COLLEGE OF MEDICINE · 2024 · $120,466

## Abstract

Project Summary
Breast cancer has been the most prevalent cancer and the second leading cause of cancer-related death in
American women for many years. Immune checkpoint inhibitors (ICIs) targeting checkpoint proteins such as
programmed cell death protein 1 (PD1) resulted in durable clinical remissions in a subset of cancer patients,
including breast cancer. However, most patients didn’t show a response to ICI treatment, urging the need for
novel biomarkers that can predict patient response and therapeutic targets that can improve the efficacy and
durability of ICIs. The goal of this proposal is to investigate how to overcome the ICI resistance. My preliminary
data showed that interferon (IFN) -alpha and -gamma signaling are enriched in the tumor and blood neutrophils
of nonresponders to ICIs. The central hypothesis of this proposal is that tumor-educated neutrophils with
increased IFN signaling mediate breast cancer resistance to ICIs, and can be used as predictive biomarkers.
During the K99 phase, I will explore the impact of neutrophil-restricted IFN signaling on tumor response to ICIs
and characterize the neutrophil-specific interferon-stimulated gene (ISG) signature (Aim 1). Since we found that
ISGs in peripheral blood neutrophils can predict breast cancer response to anti-PD1 therapy, I will determine if
blood neutrophil ISGs signature can serve as a biomarker in other cancer types and human patient samples
from the clinic and clinical trials (Aim 2, K99 and R00). Finally, I will study the neutrophil IFN signaling in regulating
immune memory and durable response to ICIs (Aim 3, R00). Upon successful completion of the Specific Aims,
this translational study will extend our knowledge of neutrophil IFN signaling and provide novel biomarkers for
the ICI therapy and therapeutic targets to overcome the ICI resistance.
My overall career goal is to establish an independent translational cancer research group that will improve
understanding of cancer development, identify novel effective therapies, and train the next generation of cancer
researchers. This proposed research in the K99 phase will take place in the Lester and Sue Smith Breast Center
at Baylor College of Medicine, a highly collaborative and multidisciplinary environment with strong integration of
basic, translational, and clinical research. The institution is dedicated to the career development of postdoctoral
trainees, and provides a variety of training venues including bioinformatics and immunology, weekly seminars,
R&D workshops, journal clubs, and the annual retreat. BCM is part of the Texas Medical Center, the largest
medical city in the world consisting of over 60 medical institutions and hospitals, which offers me enormous
opportunities for training and collaboration. Finally, I will meet with Drs. Rosen and Zhang weekly to discuss my
projects besides our weekly lab meetings and have a formal committee meeting every three months to discuss
my progress and receive feedback. I am a...

## Key facts

- **NIH application ID:** 10862583
- **Project number:** 5K99CA279899-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yang Gao
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $120,466
- **Award type:** 5
- **Project period:** 2023-06-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862583

## Citation

> US National Institutes of Health, RePORTER application 10862583, Harnessing neutrophils to improve the efficacy of immune checkpoint inhibitors in breast cancer (5K99CA279899-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10862583. Licensed CC0.

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