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

项目总结 研究：抗药性限制抗PD-1治疗癌症疗效：只有40%的黑色素瘤 患者对这种疗法有反应，其中一半会产生抵抗力。抵抗力可能来自以下几个方面 机制包括癌细胞获得突变或免疫抑制免疫侵袭肿瘤 细胞。迫切需要了解耐药机制以开发新的免疫疗法 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髓系群体，可靶向克服耐药性 敬抗PD-1。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是如何 应用单细胞RNA测序和原位杂交技术对小鼠模型中免疫抑制髓系群体的影响 应用多重免疫荧光法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，髓系细胞可以克服对抗PD-1的耐药性。这项研究将定义 如何根据患者独特的癌症突变和浸润性进行个性化免疫治疗 免疫抑制髓系细胞，长期目标是改善对免疫治疗的反应。 候选人和导师：The PI，Brian Miller，医学博士，是一名肿瘤学家和癌症免疫学家 达纳-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%的人在临床实践中照顾癌症患者。他的目标是领导一项独立的学术研究 髓系细胞在肿瘤微环境中作用的实验室研究及治疗进展 克服免疫疗法耐药性的策略。他将通过以下方式追求这一目标：1)在 单细胞RNA测序数据的产生和分析；2)成为髓系细胞生物学和 开发体外和体内功能分析；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。他将得到博士的指导。 Arlene Sharpe，肿瘤免疫学专家，以及一个强大的具有专业知识的科学咨询委员会 在计算生物学、髓系细胞和转化免疫疗法方面：彼得·哈尔琴科博士、乔恩·卡根博士、 还有史蒂芬·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 他需要在肿瘤微环境和单细胞分析方面开拓自己独特的利基市场所需的专业知识 肿瘤浸润性髓系细胞的功能解剖。 环境：米勒博士将在哈佛医学院进行这项研究，并利用 哈佛大学、达纳-法伯癌症研究所和布罗德研究所的研究和教学环境。在……里面 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。米勒博士有权获得 成功完成他提出的研究并过渡到独立的必要工具。

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.