Interrogating the role for ATP-dependent chromatin remodeling complexes in immune response

探究 ATP 依赖性染色质重塑复合物在免疫反应中的作用

• 批准号: 9757510
• 负责人: Dawn E Comstock
• 金额: $ 3.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757510
• 关键词: ATAC-seq; ATP Hydrolysis; Biological Assay; Biological Models; Biology; CRISPR screen; CRISPR/Cas technology; CTLA4 gene; Cell Line; Cell Proliferation; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clear cell renal cell carcinoma; Clinical; Complex; DNA; Data; Epigenetic Process; Family; Foundations; Gene Deletion; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Goals; Human; Immune; Immune response; Immunotherapy; Individual; Interferon Type II; Interferon-beta; Interferons; Investigation; Laboratories; Location; Malignant Neoplasms; Mediating; Melanoma Cell; Molecular; Molecular Conformation; Mutate; Mutation; Nucleosomes; Pathway interactions; Patients; Positioning Attribute; Regulation; Relapse; Research; Resistance; Resistance development; Role; Structure; Sucrose; TNF gene; Therapeutic; anti-PD-1; anti-PD-L1; anti-PD1 therapy; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chromatin remodeling; clinical efficacy; cytokine; epigenetic regulation; immune checkpoint blockade; improved; in vivo; in vivo Model; interest; loss of function; melanoma; mouse model; neoplastic cell; predictive marker; programs; resistance mechanism; response; success; therapy resistant; tool; transcriptome sequencing; transcriptomics; treatment strategy; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Desipte the marked clinical success of treating cancer with immunotherapies, including anti-PD-1, anti-CTLA-4 and anti-PD-L1, the majority of patients do not respond to these treatments or relapse following initial response. Research efforts to analyze the role of tumor cell intrinsic mechanisms that mediate responsiveness to immunotherapy treatments offer great potential to improve these treatment strategies. One layer of cell intrinsic regulation that remains to be thorughly analyzed is the epigenetic profile of tumor cells and how this level of regulation impacts the overall responsiveness to immunotherapy. Epigenetic regulation can be achieved by the structural remodelling of the chromatin by distinct complexes such as the mammalian Switch/Sucrose Non-Fermentable (mSWI/SNF) ATP-dependent chromatin remodelling complex. mSWI/SNF uses energy generated from ATP-hydrolysis to alter chromatin through many mechanisms including ejection, destabilisation and restructuring of nucleosomes allowing for changes in the accessibility of distinct genetic regions resulting in context specific, highly regulated gene expression. The mSWI/SNF complex is of particular interest because data from an in vivo CRISPR screen in B16 melanoma demonstrated that deletion of genes encoding select subunits of the mSWI/SNF each conferred resistance to anti-PD-1 treatment (Manguso et. al, 2017). Through this proposal we will conduct a comprehensive analysis of all mSWI/SNF subunits to determine their role in regulating responsiveness of melanoma to anti-PD-1 immunotherapy, and deeply interrogate the mechanistic role of both conformations of mSWI/SNF, BAF and PBAF, in melanoma by analyzing the genomic location of these complexes, changes in chromatin accessiblity and the resulting transcriptomic changes which impact cellular processes. As a whole, this proposal offers great potential to impact the fundamental understanding of SWI/SNF biology as well as inform our understanding of epigenetic regulation as it relates to immunotherapy responsiveness.

项目摘要/摘要 希望用包括抗PD-1、抗CTLA-4在内的免疫疗法治疗癌症取得显著临床成功 和抗PD-L1，大多数患者对这些治疗没有反应或在初次治疗后复发 回应。研究努力分析调节反应的肿瘤细胞内在机制的作用 免疫疗法为改进这些治疗策略提供了巨大的潜力。一层细胞 有待深入分析的内在调节是肿瘤细胞的表观遗传学特征，以及这是如何 调控水平影响对免疫治疗的整体反应。表观遗传调控可以是 通过不同的复合体(如哺乳动物)对染色质进行结构改造而实现的 Switch/蔗糖不可发酵(mSWI/SNF)依赖于ATP的染色质重塑复合体。MSWI/SNF 利用ATP水解产生的能量通过包括喷射在内的许多机制改变染色质， 核小体的不稳定和重组允许改变不同基因的可及性 导致上下文特定的、高度调控的基因表达的区域。MSWI/SNF复合体是特别的 感兴趣是因为来自B16黑色素瘤体内CRISPR筛查的数据显示基因缺失 编码mSWI/SNF的选择亚基，每个亚基都对抗PD-1治疗产生抗性(Manguso et.艾尔， 2017年)。通过这项提案，我们将对所有mSWI/SNF亚基进行全面分析，以确定 它们在调节黑色素瘤对抗PD-1免疫治疗的反应性中的作用，并深入探讨 从基因组角度分析mSWI/SNF、BAF和PBAF两种构象在黑色素瘤中的作用 这些复合体的位置、染色质可及性的变化以及由此导致的转录变化 影响细胞过程。总体而言，这项提议提供了巨大的潜力来影响基本的 对SWI/SNF生物学的理解以及对表观遗传调控的理解 免疫治疗的反应性。