Single cell epigenomics in cancer immunity and immunotherapy

单细胞表观基因组学在癌症免疫和免疫治疗中的应用

• 批准号: 9753174
• 负责人: Ansuman Satpathy
• 金额: $ 16.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753174
• 关键词: 3-Dimensional; ATAC-seq; Advisory Committees; Aftercare; Antigens; Basal cell carcinoma; Basic Science; Biological Assay; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cancer Biology; Cancer Patient; Cells; Chromatin; Clinical; Clinical Pathology; Clinical Treatment; Clinics and Hospitals; Clonality; Core Facility; Custom; Data; Dermatology; Disease remission; Doctor of Medicine; Doctor of Philosophy; Engineering; Enhancers; Environment; Epigenetic Process; Functional disorder; Future; Genes; Genomics; Goals; High-Throughput Nucleotide Sequencing; Human; Immune; Immune system; Immunity; Immunology; Immunotherapy; Individual; Malignant Neoplasms; Maps; Measurement; Medical Residency; Medicine; Mentors; Molecular; Pathway interactions; Patients; Physicians; Positioning Attribute; Process; Program Development; Protocols documentation; Records; Regulation; Regulatory Element; Regulatory Pathway; Relapse; Research; Research Infrastructure; Residencies; Resistance; Resolution; Ribonucleoproteins; SLEB2 gene; Sampling; Scientist; Signal Transduction; Site; Skin Cancer; Software Tools; Specificity; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Testing; Time; Training Programs; Universities; Washington; cancer cell; cancer immunotherapy; cancer subtypes; career; career development; chimeric antigen receptor T cells; clinical care; education resources; epigenome; epigenomics; genome editing; genome sciences; improved; innovation; insight; medical schools; neoplasm immunotherapy; next generation; novel; novel sequencing technology; patient subsets; personalized immunotherapy; personalized strategies; professor; profiles in patients; promoter; response; skills; therapy resistant; treatment response; tumor

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year career development program for Dr. Ansuman Satpathy, M.D., Ph.D. with the goal of preparing him for an independent research career as an academic physician-scientist. Dr. Satpathy completed his M.D. and Ph.D. in Immunology at Washington University in St. Louis and his medical residency in Clinical Pathology at Stanford Hospital and Clinics. During his residency, Dr. Satpathy performed basic science research in the lab of Dr. Howard Chang, who is a Professor of Dermatology and Director of the Center for Excellence in Genome Science at Stanford University. Dr. Chang is an expert in the fields of genomics and cancer biology and has previously served as a mentor to many physician-scientists who have transitioned to independent positions in academic medicine. Stanford University provides an outstanding environment for Dr. Satpathy to develop his independent research career. First, Dr. Satpathy's Advisory Committee comprised of Drs. Mackall, Montine, Greenleaf, and Galli has diverse and extensive scientific expertise relevant to all aspects of this proposal and highly successful track records as scientific mentors. Second, Dr. Satpathy will acquire additional scientific and professional skills through educational resources available through the School of Medicine and Office of Postdoctoral Affairs. Third, the research infrastructure within the Chang lab and neighboring core facilities will enable Dr. Satpathy to efficiently perform the scientific aims described in this proposal. The long-term goal of the proposed research is to study the epigenetic basis for immunotherapy resistance in patients with advanced basal cell carcinoma (BCC). Clinical immunotherapies that enhance the ability of T lymphocytes to destroy cancer cells have demonstrated remarkable efficacy in advanced skin cancers, but only a subset of patients respond to therapy. During Dr. Satpathy’s brief time in the Chang lab, he developed novel sequencing technologies which enable epigenomic studies in primary immune cells from patients with newfound resolution. In Aim 1, we will perform simultaneous epigenome and T cell receptor sequencing in single cells to identify epigenetic signatures of T cell dysfunction in tumor-specific CD8+ tumor- infiltrating T lymphocytes (TILs). This integrative approach will separate regulatory networks in clonal tumor- specific T cells from background non-reactive T cells in the same patient. In Aim 2, we will use this technique to identify regulatory signatures in CD8+ TILs that are associated with immunotherapy resistance in BCC patients receiving anti-PD-1 immunotherapy. In Aim 3, we will engineer durable T cell immunotherapy responses using genome editing of regulatory sites in primary T cells. Finally, we will facilitate the dissemination of these findings by freely distributing protocols and data and releasing custom software tools. We anticipate that these results will lead to novel insights into the molecular regulation of immunotherapy resistance and serve as an effective training program for Dr. Satpathy to launch his independent career as an academic physician scientist.

项目摘要/摘要 该提案概述了博士的五年职业发展计划。 为他作为学术医师科学家的独立研究职业做准备 在圣路易斯的华盛顿大学完成了他的医学博士学位 斯坦福医院和诊所的临床病理学。 皮肤病学教授兼Forfor中心主任霍华德·昌（Howard Chang）博士的研究 斯坦福大学基因组科学卓越。 癌症生物学，以前曾担任过许多过渡到的科学家科学家的导师 斯坦福大学的独立职位。 SATPATH为了发展他的独立研究职业。 Mackall，Montine，Greenleaf和Galli具有多样的科学专业知识 在科学导师中，这一建议和非常成功的记录将获得Satpathy博士 通过教育资源提供的其他科学和专业技能 医学和博士后事务办公室。 邻近的核心设施将使博士能够有效执行此处描述的科学目的 提议。 晚期基底细胞癌（BCC）的抗药性。 脑细胞破坏癌细胞的能力在晚期皮肤中表现出了显着的功效 癌症，但只有一部分患者对治疗有反应。 开发了新型的测序技术，该技术能够从原代免疫细胞中进行表观基因组研究 AIM 1中有新发现的患者，我们将执行表观基因组 单个细胞中的测序以鉴定肿瘤特异性CD8+肿瘤中T细胞功能障碍的表观遗传特征 浸润T淋巴细胞（TILS）。 在AIM 2中，来自背景的特定T细胞非反应性T细胞 确定CD8+ TIL中与BCC患者免疫疗法抗性相关的调节签名签名 在AIM 3中接受抗PD-1免疫疗法。 原代T细胞中调节位点的基因组编辑。 通过自由分发协议和数据，并保证定制软件工具。 将导致Tonovel的见解对免疫疗法抗性的分子调节，并作为有效 博士的培训计划启动他作为学术医师科学家的独立职业。