Dissecting temporal and spatial dynamics of immunotherapy resistance

项目摘要 免疫检查点抑制剂（ICI）目前被用作复发性或转移性乳腺癌患者的一线治疗。 头颈部鳞状细胞癌（HNSCC），然而，只有六分之一的患者有反应。如何 肿瘤免疫微环境的组成和空间组织与HNSCC中ICI疗效相关 目前还知之甚少。已知的是，癌症是动态的，在时间和空间上不断演变， 对治疗压力的反应，有建筑支持表明，治疗评估更 与治疗前组织的评估相比，ICI反应的预测。在本提案中，我们将采用创新的 单细胞测序和成像方法，以回答阻碍头部和 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抗性。 目的1将区分原发组织中与ICI耐药相关的肿瘤细胞程序， 测量循环肿瘤细胞中这些基因的改变。目标2将定义T和B细胞亚群如何 和空间结构的变化与ICI启动和如何改变涉及ICI抗性。完成 这些指导目标将为开发改进的预测生物标志物的长期目标奠定基础。 ICI反应和识别组合疗法的新靶点。这份职业发展建议书 提出了一个五年计划，以实现概述的科学目标，以及详细的培训计划 以确保候选人过渡到研究独立。候选人是一名讲师， 马萨诸塞州哈佛医学院耳鼻咽喉头颈外科 马萨诸塞州综合医院。培训目标，其中包括实践经验，课程和 以免疫基因组学为重点的研讨会，建立在候选人先前在癌症方面的研究经验基础上 基因组学和头颈癌外科医生的临床经验。导师将由思想提供 单细胞成像和测序、生物信息学、生物标志物科学和癌症免疫学领域的领导者 包括Shannon Stott博士、基思Flaherty博士和Nir Hacohen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.