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.

项目摘要 乳腺癌一直是最普遍的癌症，也是癌症相关死亡的第二大原因 美国妇女多年。免疫检查点抑制剂（ICI）靶向检查点蛋白，例如 程序性细胞死亡蛋白1（PD1）导致一部分癌症患者的临床减免持久， 包括乳腺癌。但是，大多数患者没有表现出对ICI治疗的反应，敦促需要 可以预测患者反应和治疗靶标的新型生物标志物可以提高效率和 ICIS的持续时间。该提案的目的是研究如何克服ICI耐药性。我的初步 数据表明，干扰素（IFN）-Alpha和-gamma信号传导富含肿瘤和血液中性粒细胞 对ICIS的无反应。该提议的中心假设是 增加了IFN信号对ICI的乳腺癌耐药性增加，可以用作预测生物标志物。 在K99阶段，我将探讨中性粒细胞限制的IFN信号对ICIS肿瘤反应的影响 并表征中性粒细胞特异性干扰刺激的基因（ISG）特征（AIM 1）。因为我们发现 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，我将确定是否是否 血液中性粒细胞签名可以用作其他癌症类型的生物标志物和人类患者样本 来自诊所和临床试验（AIM 2，K99和R00）。最后，我将在调节中研究中性粒细胞IFN信号传导 免疫记忆和对ICIS的持久反应（AIM 3，R00）。成功完成具体目标后， 这项翻译研究将扩展我们对中性粒细胞IFN信号传导的了解，并为 ICI疗法和治疗靶标，以克服ICI耐药性。 我的整体职业目标是建立一个独立的翻译癌症研究小组，以改善 了解癌症发展，确定新颖的有效疗法并训练下一代癌症 研究人员。这项在K99阶段提出的研究将在Lester和Sue Smith乳房中心进行 在贝勒医学院（Baylor Medicine），是一个高度协作和多学科的环境 基础，翻译和临床研究。该机构致力于博士后的职业发展 受训者，并提供各种培训场所，包括生物信息学和免疫学，每周的半手 研发研讨会，期刊俱乐部和年度务虚会。 BCM是德克萨斯医疗中心的一部分，最大 世界上的医疗城市由60多个医疗机构和医院组成，这为我提供了巨大的 培训与协作的机会。最后，我将与博士见面。罗森和张每周讨论我的 除我们的每周实验室会议外，还举行一次正式委员会会议，每三个月进行一次正式委员会会议进行讨论 我的进度并收到反馈。我也得到了病人的拥护者和其他合作者的支持。通过 在我的K99/R00应用程序中提出的培训和研究计划，我将获得知识和技能 将极大地提高我作为独立研究者的科学生涯的能力。