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

利用中性粒细胞提高免疫检查点抑制剂在乳腺癌中的疗效

基本信息

批准号：
10644508
负责人：
Yang Gao
金额：
$ 11.73万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644508
关键词：
Adoptive Transfer Advocate American Basic Science Bioinformatics Biological Biological Markers Blood specimen Breast Breast Cancer Model Breast Cancer Patient Cancer Etiology Cancer Patient Cell physiology Cells Cessation of life Cities Clinic Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Data Dedications Development Distant Educational workshop Environment Feedback Foundations Genes Goals Hospitals Human IFNAR1 gene IFNGR1 gene Immune Immune checkpoint inhibitor Immunity Immunologic Memory Immunology Immunophenotyping Impairment In Vitro Institution Interferon alpha Interferons Journals Knock-out Knowledge Knowledge acquisition Ligands Macrophage Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Medical center Medicine Mesothelioma Modeling Mouse Mammary Tumor Virus Mus Mutation Myelogenous Outcome Parabiosis Patients Phase Postdoctoral Fellow Pre-Clinical Model Prediction of Response to Therapy Proteins Renal Cell Carcinoma Research Research Personnel Resistance Role Sampling Signal Transduction Site Spatial Distribution T-Cell Proliferation T-Lymphocyte Testing Texas Therapeutic Intervention Training Translational Research Tumor Subtype Woman anti-PD-1 anti-PD1 therapy anti-tumor immune response cancer cell cancer type career career development cell type checkpoint therapy chemotherapy clinical application clinical biomarkers clinical remission college effective therapy experimental study gain of function genetic signature immune function improved in vivo inhibitor therapy loss of function malignant breast neoplasm meetings multidisciplinary neoplastic cell neutrophil next generation novel novel marker patient response peripheral blood polyoma middle tumor antigen predicting response predictive marker programmed cell death protein 1 receptor research and development responders and non-responders response skills therapeutic development therapeutic target training opportunity transcriptome transcriptomics translational cancer research translational study triple-negative invasive breast carcinoma tumor

项目摘要

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 also supported by a patient advocate and other collaborators. Through the training and research plan proposed within my K99/R00 application, I will acquire knowledge and skills which will greatly improve my ability to launch my scientific career as an independent investigator.

项目总结