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: 10374916
• 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/10374916
• 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 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; Recurrence; Regimen; Research; Research Personnel; Resistance; Resolution; Retrospective cohort; Sampling; Science; Selection for Treatments; Spatial Distribution; Surgeon; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Training; Training Programs; Tumor-infiltrating immune cells; cancer care; cancer genomics; 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; survival outcome; tertiary lymphoid organ; therapeutic target; transcriptome; transcriptome sequencing; 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.

项目概要 免疫检查点抑制剂（ICI）现在被用作复发或转移性患者的一线治疗 然而，只有六分之一的患者对头颈鳞状细胞癌（HNSCC）有反应。 肿瘤免疫微环境的组成和空间组织与 HNSCC 的 ICI 疗效相关 目前人们对癌症的了解还很少，癌症是动态的，随时间和空间的变化而变化。 对治疗压力的反应，建立支持表明治疗评估更重要 与评估治疗前组织相比，可以预测 ICI 反应。在本提案中，我们将应用创新技术。 单细胞测序和成像方法可以回答阻碍头部和脑部疾病进展的关键问题 颈部癌症护理：肿瘤和免疫细胞的时空演化如何影响 ICI 耐药性。 目标 1 将区分与原代组织中 ICI 耐药相关的肿瘤细胞程序，并连续 测量循环肿瘤细胞中这些基因的变化，目标 2 将定义 T 细胞和 B 细胞亚群的变化。 空间结构随着 ICI 的启动而变化，以及变化与 ICI 抵抗的完成有何关系。 这些指导目标将为开发改进的预测性生物标志物的长期目标奠定基础。 ICI 响应并确定组合疗法的新目标。 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 确保候选人过渡到研究独立性。 马萨诸塞州哈佛医学院耳鼻喉头颈外科 马萨诸塞州总医院的培训目标包括实践经验、课程作业和 以免疫基因组学为重点的研讨会，以候选人之前的癌症研究经验为基础 作为头颈癌症外科医生的基因组学和临床经验将由思想提供指导。 单细胞成像和测序、生物信息学、生物标记科学和癌症免疫学领域的领导者 包括 Shannon Stott 博士、Keith Flaherty 医学博士和 Nir ​​Hacohen 博士的主要导师团队 在马萨诸塞州总医院癌症中心。