Dissecting temporal and spatial dynamics of immunotherapy resistance

项目总结 免疫检查点抑制剂(Ici)现在被用作复发或转移患者的一线治疗药物。 头颈部鳞状细胞癌(HNSCC)，但只有六分之一的患者有反应。怎么了？ 肿瘤免疫微环境的组成和空间组织与HNSCC的ICI疗效相关 目前人们对此知之甚少。已知的是，癌症是动态的，在时间和空间上演变 对治疗压力的反应，越来越多的支持表明，对治疗评估的支持更多 对ICI反应的预测优于对治疗前组织的评估。在这份提案中，我们将应用创新 单细胞测序和成像方法回答阻碍头颅和脑部疾病进展的关键问题 颈部癌症护理：肿瘤和免疫细胞的空间和时间演变如何影响ICI抵抗。 目标1将区分与ICI耐药相关的原发组织和序列中的肿瘤细胞程序 测量循环肿瘤细胞中这些基因的变化。目标2将定义T和B细胞亚群如何 空间构筑随ICI的启动而改变，以及改变与ICI抵抗的关系。完成 这些指导目标将为开发改进的预测生物标记物的长期目标奠定基础。 ICI反应和确定组合疗法的新靶点。这份职业发展建议 提出了一个五年计划，以实现概述的科学目标和详细的培训计划 以确保候选人向研究独立的过渡。应聘者是一名教师 马萨诸塞州哈佛医学院耳鼻喉科头颈外科 麻省总医院。培训目标，包括实践经验、课程设置和 研讨会的重点是免疫基因组学，以候选人以前在癌症方面的研究经验为基础 基因组学和作为头颈部癌症外科医生的临床经验。思想将提供良师益友 在单细胞成像和测序、生物信息学、生物标记物科学和癌症免疫学方面处于领先地位 包括香农·斯托特博士、基思·弗莱厄蒂医学博士和尼尔·哈科恩博士的主要指导团队 在马萨诸塞州总医院癌症中心。

PROJECT SUMMARY Immune checkpoint inhibitors (ICI) are now used as first line therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet, only one out of six patients respond. How the composition and spatial organization of the tumor immune microenvironment relates to ICI efficacy in HNSCC is currently poorly understood. What is known, is that cancers are dynamic, evolving temporally and spatially in response to therapeutic pressures, with building support suggesting that on treatment assessment is more predictive of ICI response than assessment of pre-treatment tissue. In this proposal we will apply innovative single cell sequencing and imaging approaches to answer a critical question impeding progress in head and neck cancer care: how the spatial and temporal evolution of tumor and immune cells impacts ICI resistance. Aim 1 will distinguish tumor cell programs that associate with ICI resistance in primary tissue and serially measure alterations in these genes in circulating tumor cells. Aim 2 will define how T and B cell subpopulations and spatial architecture change with ICI initiation and how alterations relate to ICI resistance. Completion of these mentored aims will set the stage for the long term goal of developing improved predictive biomarkers of ICI response and identifying new targets for combinatorial therapies. This career development proposal presents a five-year plan to both accomplish the outlined scientific aims as well as a detailed training program to ensure the candidate’s transition to research independence. The candidate is an Instructor in Otolaryngology-Head and Neck Surgery at Harvard Medical School, Massachusetts Eye and Ear and Massachusetts General Hospital. The training aims, which include hand on experience, coursework and seminars focused on immunogenomics, build on the candidate’s previous research experience in cancer genomics and clinical experience as a head and neck cancer surgeon. Mentorship will be provided by thought leaders in single cell imaging and sequencing, bioinformatics, biomarker science, and cancer immunology including the primary mentorship team of Dr. Shannon Stott, PhD, Keith Flaherty, MD and Nir Hacohen, PhD at Massachusetts General Hospital Cancer Center.