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: 10425380
• 负责人: Brian C Miller
• 金额: $ 19.46万
• 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/10425380
• 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; Institutes; 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; Somatic Mutation; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Tumor-infiltrating immune cells; Work; anti-PD-1; anti-PD1 therapy; base; cancer cell; cancer therapy; career development; cell killing; clinical efficacy; clinical practice; 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; 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.

项目摘要 研究：治疗耐药性限制抗PD-1治疗癌症的疗效：仅40%的黑色素瘤 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免疫的肿瘤浸润 细胞迫切需要了解耐药机制，以开发新的免疫抑制剂 战略来克服它们。基于我们的初步数据，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，可以靶向克服耐药性， 抗PD-1抗体为了验证这一假设，在目标1中，我们将确定临床定义的耐药突变如何影响耐药基因的表达。 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， 使用多重免疫荧光法对人类黑色素瘤进行活检。在目标2中，我们将确定如何抑制 骨髓细胞可以克服对抗PD-1的抗性，具有机制小鼠研究。这项研究将定义 如何根据患者独特的癌症突变和浸润性疾病进行个性化免疫治疗 免疫抑制性骨髓细胞，长期目标是改善对免疫疗法的反应。 候选人和导师：PI，Brian米勒，医学博士，是一名肿瘤学家和癌症免疫学家， 丹娜-法伯癌症研究所和哈佛医学院。他90%的时间都花在翻译研究上 10%用于癌症患者的临床护理。他的目标是领导一个独立的学术研究 实验室研究骨髓细胞在肿瘤微环境中的功能， 克服免疫疗法抵抗的策略。他将通过以下方式实现这一目标：1）发展 生成和分析单细胞RNA测序数据; 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，以扩大他的计算和统计背景。他将由博士指导。 阿琳夏普，肿瘤免疫学专家，沿着一个强大的科学咨询委员会与专业知识 在计算生物学、骨髓细胞和翻译免疫疗法方面：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， 专业知识需要在肿瘤微环境的单细胞分析中发展自己独特的利基， 肿瘤浸润性骨髓细胞的功能性解剖。 环境：米勒博士将在哈佛医学院进行这项研究， 研究和教学环境在哈佛，达纳法伯癌症研究所，和广泛的研究所。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。米勒医生有权限 成功完成他提议的研究和向独立过渡的必要工具。