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

• 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
• 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

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.

项目概要 乳腺癌是最常见的癌症，也是癌症相关死亡的第二大原因 美国女性多年来。免疫检查点抑制剂（ICIs）针对检查点蛋白，例如 程序性细胞死亡蛋白 1 (PD1) 使一部分癌症患者获得持久的临床缓解， 包括乳腺癌。然而，大多数患者对 ICI 治疗没有表现出反应，这表明需要 可以预测患者反应的新型生物标志物和可以提高疗效的治疗目标 ICI 的耐用性。该提案的目标是研究如何克服 ICI 阻力。我的初步 数据显示，干扰素（IFN）-α和-γ信号在肿瘤和血液中性粒细胞中富集 对 ICI 无反应者的比例。该提案的中心假设是肿瘤教育的中性粒细胞 增加的 IFN 信号介导乳腺癌对 ICI 的耐药性，可用作预测生物标志物。 在K99阶段，我将探讨中性粒细胞限制性IFN信号传导对肿瘤对ICIs反应的影响 并表征中性粒细胞特异性干扰素刺激基因 (ISG) 特征（目标 1）。自从我们发现 外周血中性粒细胞中的 ISG 可以预测乳腺癌对抗 PD1 治疗的反应，我将确定是否 血液中性粒细胞 ISG 特征可作为其他癌症类型和人类患者样本中的生物标志物 来自临床和临床试验（目标 2、K99 和 R00）。最后，我将研究中性粒细胞干扰素信号传导的调节 免疫记忆和对 ICI 的持久反应（目标 3，R00）。在成功完成具体目标后， 这项转化研究将扩展我们对中性粒细胞干扰素信号传导的了解，并为以下疾病提供新的生物标志物： ICI 疗法和克服 ICI 耐药性的治疗靶点。 我的总体职业目标是建立一个独立的转化癌症研究小组，以改进 了解癌症的发展，确定新的有效疗法，并培养下一代癌症 研究人员。这项 K99 阶段的拟议研究将在莱斯特和苏史密斯乳腺中心进行 贝勒医学院拥有高度协作和多学科的环境， 基础、转化和临床研究。该机构致力于博士后的职业发展 学员，并提供各种培训场所，包括生物信息学和免疫学、每周研讨会、 研发研讨会、期刊俱乐部和年度静修会。 BCM 是德克萨斯医疗中心的一部分，该中心是最大的 由60多家医疗机构和医院组成的世界医疗城，为我提供了巨大的 培训和合作的机会。最后，我将与Drs见面。罗森和张每周讨论我的 除了我们每周的实验室会议之外的项目，并且每三个月举行一次正式的委员会会议来讨论 我的进步并收到反馈。我还得到了一位患者倡导者和其他合作者的支持。通过 根据我的 K99/R00 申请中提出的培训和研究计划，我将获得以下知识和技能： 将极大地提高我作为独立研究者开展科学职业生涯的能力。