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

项目摘要 在#年，乳腺癌一直是最常见的癌症，也是癌症相关死亡的第二大原因。 多年来一直是美国女性。针对检查点蛋白的免疫检查点抑制物(ICIS)，如 程序性细胞死亡蛋白1(PD1)在部分癌症患者中导致持久的临床缓解， 包括乳腺癌。然而，大多数患者对ICI治疗没有反应，敦促需要 新的生物标志物，可以预测患者的反应和治疗靶点，可以提高疗效和 ICIS的耐用性。这项提案的目的是研究如何克服ICI阻力。我的初选 数据显示，干扰素(干扰素)-α和-γ信号在肿瘤和血液中性粒细胞中丰富。 对ICIS无反应的人。这一提议的中心假设是，受肿瘤教育的中性粒细胞与 干扰素信号增强介导乳腺癌对ICIS的耐药，可作为预测生物标记物。 在K99期，我将探讨中性粒细胞限制性干扰素信号对肿瘤对ICIS反应的影响 和中性粒细胞特异性干扰素刺激基因(ISG)的特征(目标1)。因为我们发现 外周血中性粒细胞中的ISGS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ISGs信号可作为其他癌症类型和人类患者样本的生物标记物 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在调控中的作用 免疫记忆和对ICIS的持久反应(目标3，R00)。在成功完成特定目标后， 这项翻译研究将扩展我们对中性粒细胞干扰素信号转导的知识，并为 ICI治疗及克服ICI抵抗的治疗靶点。 我的总体职业目标是建立一个独立的翻译癌症研究小组，该小组将改善 了解癌症的发展，确定新的有效治疗方法，并培训下一代癌症 研究人员。K99阶段的这项拟议研究将在莱斯特和苏·史密斯乳房中心进行 在贝勒医学院，高度协作的多学科环境与 基础研究、转化研究和临床研究。该机构致力于博士后的职业发展。 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、 研发工作坊、杂志俱乐部和年度静修。BCM是德克萨斯医疗中心的一部分，该中心是世界上最大的 世界上由60多家医疗机构和医院组成的医疗城市，这为我提供了巨大的 培训和协作的机会。最后，我将每周与罗森博士和张博士会面，讨论我的 除了我们每周的实验室会议之外的项目，并每三个月召开一次正式的委员会会议来讨论 我的进度和接收反馈。我还得到了一位患者权益倡导者和其他合作者的支持。穿过 在我的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一名独立研究员开始我的科学生涯的能力。

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.