Targeting Unique Meyloid Populations to Overcome Anti-PD-1 Resistance Conferred by Specific Cancer Mutations

靶向独特的髓样细胞群以克服特定癌症突变带来的抗 PD-1 耐药性

• 批准号: 10655545
• 负责人: Brian C Miller
• 金额: $ 28.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655545
• 关键词: Advisory Committees; Antigen Presentation; Biological Assay; Biopsy; Cell Line; Cells; Cellular biology; Clinical; Combination immunotherapy; Combined Modality Therapy; Computational Biology; Dana-Farber Cancer Institute; Data; Data Set; Development; Development Plans; Dissection; Doctor of Philosophy; Educational process of instructing; Effector Cell; Ensure; Environment; Generations; Goals; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunofluorescence Immunologic; Immunologist; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Inflammatory; Laboratory Research; Laboratory Study; Lead; Link; Malignant Neoplasms; Mediating; Melanoma Cell; Mentors; Mentorship; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Oncologist; PD-1/PD-L1; Patient Care; Patients; Pattern; Population; Property; Publishing; Reagent; Regimen; Research; Research Project Summaries; Resistance; Resistance development; Series; Shapes; Somatic Mutation; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Work; anti-PD-1; anti-PD1 therapy; cancer cell; cancer therapy; career development; cell killing; clinical efficacy; clinical practice; immune cell infiltrate; immunosuppressive macrophages; improved; in vivo; individual patient; individualized medicine; medical schools; melanoma; mentoring community; mouse model; mutant; neoplastic cell; neutrophil; novel; novel therapeutics; personalized immunotherapy; personalized medicine; prevent; recruit; resistance mechanism; resistance mutation; response; single cell analysis; single-cell RNA sequencing; skill acquisition; skills; success; targeted treatment; therapy resistant; tool; translational scientist; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY Research: Therapeutic resistance limits the efficacy of anti-PD-1 therapy for cancer: only 40% of melanoma patients respond to this therapy, and half of these will develop resistance. Resistance can arise from several mechanisms including mutations acquired by cancer cells or infiltration of tumors by immunosuppressive immune cells. There is a critical need to understand resistance mechanisms to develop novel immunotherapeutic strategies to overcome them. Based on our preliminary data, we hypothesize that cancer cells with resistance mutations recruit unique immunosuppressive myeloid populations that can be targeted to overcome resistance to anti-PD-1. To test this hypothesis, in Aim 1 we will determine how clinically-defined resistance mutations impact immunosuppressive myeloid populations in mouse models using single-cell RNA-sequencing and in human melanoma biopsies using multiplex immunofluorescence. In Aim 2 we will determine how inhibition of myeloid cells can overcome resistance to anti-PD-1 with mechanistic mouse studies. This research will define how to personalize immunotherapy based on a patient’s unique cancer mutations and infiltrating immunosuppressive myeloid cells, with the long-term goal to improve responses to immunotherapy. Candidate and Mentorship: The PI, Brian Miller, MD PhD, is an oncologist and cancer immunologist at the Dana-Farber Cancer Institute and Harvard Medical School. He spends 90% of his time in translational research and 10% in clinical practice caring for patients with cancer. His goal is to lead an independent academic research laboratory studying the functions of myeloid cells in the tumor microenvironment and developing therapeutic strategies to overcome resistance to immunotherapy. He will pursue this goal by: 1) developing expertise in the generation and analysis of single-cell RNA-sequencing data; 2) becoming an expert in myeloid cell biology and developing in vitro and in vivo functional assays; 3) establishing a community of mentors and collaborators; 4) completing coursework to expand his computational and statistical background. He will be mentored by Dr. Arlene Sharpe, an expert in tumor immunology, along with a strong scientific advisory committee with expertise in computational biology, myeloid cells, and translational immunotherapy: Dr. Peter Kharchenko, Dr. Jon Kagan, and Dr. Stephen Hodi. These mentors and his career development plan will help him acquire the skills and expertise needed to develop his own distinct niche in single-cell analysis of the tumor microenvironment and functional dissection of tumor-infiltrating myeloid cells. Environment: Dr. Miller will conduct this research at Harvard Medical School and leverage the exceptional research and teaching environment at Harvard, the Dana-Farber Cancer Institute, and the Broad Institute. In addition, his network of collaborators at the Dana-Farber Cancer Institute, Broad Institute, and Bristol-Myers Squibb will provide reagents, technical assistance, and expertise to ensure his success. Dr. Miller has access to the necessary tools to successfully complete his proposed research and transition to independence.

项目概要 研究：治疗耐药性限制了抗 PD-1 疗法治疗癌症的疗效：仅占黑色素瘤的 40% 患者对这种疗法有反应，其中一半会产生耐药性。阻力可能来自几个方面 机制包括癌细胞获得的突变或免疫抑制性免疫导致的肿瘤浸润 细胞。迫切需要了解耐药机制以开发新型免疫治疗药物 克服它们的策略。根据我们的初步数据，我们假设具有耐药性的癌细胞 突变招募独特的免疫抑制性骨髓细胞群，可以有针对性地克服耐药性 抗PD-1。为了检验这一假设，在目标 1 中，我们将确定临床定义的耐药突变如何 使用单细胞 RNA 测序影响小鼠模型中的免疫抑制性骨髓细胞群体 使用多重免疫荧光进行人类黑色素瘤活检。在目标 2 中，我们将确定如何抑制 通过小鼠机制研究，骨髓细胞可以克服抗 PD-1 耐药性。这项研究将定义 如何根据患者独特的癌症突变和浸润进行个性化免疫治疗 免疫抑制性骨髓细胞，长期目标是改善免疫治疗的反应。 候选人和导师：PI 布莱恩·米勒 (Brian Miller) 医学博士、博士是肿瘤学家和癌症免疫学家 丹纳法伯癌症研究所和哈佛医学院。他90%的时间都花在转化研究上 10% 从事癌症患者的临床实践护理。他的目标是领导独立的学术研究 实验室研究肿瘤微环境中骨髓细胞的功能并开发治疗方法 克服免疫治疗耐药性的策略。他将通过以下方式实现这一目标：1）发展以下领域的专业知识： 单细胞 RNA 测序数据的生成和分析； 2) 成为骨髓细胞生物学专家 开发体外和体内功能测定； 3）建立导师和合作者社区； 4） 完成课程以扩展他的计算和统计背景。他将受到博士的指导。 Arlene Sharpe，肿瘤免疫学专家，以及强大的具有专业知识的科学顾问委员会 计算生物学、骨髓细胞和转化免疫疗法博士：Peter Kharchenko 博士、Jon Kagan 博士、 和斯蒂芬·霍迪博士。这些导师和他的职业发展计划将帮助他获得技能和 在肿瘤微环境的单细胞分析方面发展自己独特的利基所需的专业知识，以及 肿瘤浸润骨髓细胞的功能解剖。 环境：米勒博士将在哈佛医学院进行这项研究，并利用卓越的 哈佛大学、丹娜法伯癌症研究所和布罗德研究所的研究和教学环境。在 此外，他在达纳法伯癌症研究所、布罗德研究所和百时美施贵宝的合作者网络 施贵宝将提供试剂、技术援助和专业知识，以确保他的成功。米勒博士可以访问 成功完成他提议的研究并过渡到独立的必要工具。