Dissecting temporal and spatial dynamics of immunotherapy resistance

剖析免疫治疗耐药性的时空动态

• 批准号: 10584610
• 负责人: Daniel Faden
• 金额: $ 17.38万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584610
• 关键词: Architecture; B-Lymphocytes; Bioinformatics; Biological Markers; Biopsy; CD8B1 gene; Cancer Center; Cell Communication; Cell Death; Cell physiology; Cells; Clinical; Development; Disease; Doctor of Philosophy; Down-Regulation; Ear; Ensure; Environment; Evolution; Eye; Five-Year Plans; Gene Expression Alteration; General Hospitals; Genes; Genomics; Goals; Hand; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and Neck Surgery; Image; Immune; Immune checkpoint inhibitor; Immunogenomics; Immunotherapy; Knowledge; Ligands; Liquid substance; MS4A1 gene; Malignant Neoplasms; Massachusetts; Measures; Mentors; Mentorship; Methods; Microfluidics; Molecular; Monitor; Neoplasm Circulating Cells; Organizational Change; Otolaryngology; Pathway interactions; Patient-Focused Outcomes; Patients; Protocols documentation; Qualifying; Recurrence; Regimen; Research; Research Personnel; Resistance; Resolution; Retrospective cohort; Sampling; Science; Selection for Treatments; Spatial Distribution; Surgeon; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Training; Training Programs; cancer care; cancer genomics; cancer type; career development; cellular imaging; cohort; combinatorial; experience; imaging approach; imaging platform; improved; innovation; instructor; liquid biopsy; medical schools; neoplastic cell; novel; novel therapeutics; predictive marker; pressure; programs; response; single cell sequencing; single-cell RNA sequencing; solid state; spectrograph; survival outcome; tertiary lymphoid organ; therapeutic target; therapy resistant; transcriptome; transcriptome sequencing; treatment response; tumor; tumor immunology; tumor-immune system interactions

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.

项目摘要 免疫检查点抑制剂（ICI）现在用作复发或转移性患者的第一线治疗 头部和颈部鳞状细胞癌（HNSCC），但六分之一的患者中只有一名反应。如何 与HNSCC中ICI效率有关的肿瘤免疫微环境的组成和空间组织 目前了解不足。已知的是，癌症是动态的，在临时和空间上演变 对热压力的反应，并在建筑支持下表明治疗评估更多 预测ICI反应比评估预处理组织的评估。在此提案中，我们将应用创新 单细胞测序和成像方法，以回答阻碍头部进展的关键问题 颈部癌症护理：肿瘤和免疫细胞的空间和暂时演变如何影响ICI耐药性。 AIM 1将区分与原代组织中与ICI抗性相关的肿瘤细胞程序和串行 测量循环肿瘤细胞中这些基因的改变。 AIM 2将定义T和B细胞的亚群 随着ICI计划的变化，空间架构以及与ICI抗性有关的变化如何变化。完成 这些修改的目标将为建立改进的预测生物标志物的长期目标奠定基础 ICI反应并确定组合疗法的新靶标。这个职业发展建议 提出了一个五年计划，既要完成概述的科学目标，又要完成详细的培训计划 确保候选人过渡到研究独立性。候选人是 哈佛医学院，马萨诸塞州的眼睛和耳朵的耳鼻喉科头和颈部手术 马萨诸塞州综合医院。培训目的，包括经验，课程和 焦点是免疫基因组学的半手，基于候选人先前在癌症领域的研究经验 作为头颈癌外科医生的基因组学和临床经验。指导将由思想提供 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的领导者 包括Shannon Stott博士，博士，医学博士Keith Flaherty和PhD Nir ​​Hacohen的主要攻表团队 在马萨诸塞州综合医院癌症中心。