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: 9978546
• 负责人: Dawn E Comstock
• 金额: $ 3.68万
• 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/9978546
• 关键词: ATAC-seq; ATP Hydrolysis; Biological Assay; Biological Models; Biology; CRISPR screen; CRISPR/Cas technology; 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; Tumor-infiltrating immune cells; anti-CTLA4; 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.

项目总结/摘要 期望通过免疫疗法（包括抗PD-1、抗CTLA-4）治疗癌症取得显著的临床成功 和抗PD-L1，大多数患者对这些治疗没有反应或在初始治疗后复发 反应分析肿瘤细胞内在机制介导反应性的作用的研究工作 免疫疗法为改善这些治疗策略提供了巨大的潜力。一层细胞 仍然需要彻底分析的内在调控是肿瘤细胞的表观遗传特征，以及这种表观遗传特征如何影响肿瘤细胞的生长。 调节水平影响对免疫疗法的总体反应性。表观遗传调节可以是 通过不同的复合物如哺乳动物的染色质的结构重塑来实现 转换/蔗糖非发酵（mSWI/SNF）ATP依赖性染色质重塑复合物。mSWI/SNF 利用ATP水解产生的能量通过许多机制改变染色质，包括排出， 核小体的不稳定和重组允许不同遗传物质的可及性的改变， 导致背景特异性、高度调节的基因表达的区域。mSWI/SNF复合物特别是 因为来自B16黑素瘤体内CRISPR筛选的数据表明基因缺失 编码mSWI/SNF的选择亚基各自赋予对抗PD-1治疗的抗性（Manguso et. Al， 2017年）。通过本提案，我们将对所有mSWI/SNF子单位进行全面分析，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，并深入探讨了 mSWI/SNF的两种构象BAF和PBAF在黑色素瘤中的机制作用，通过分析基因组 这些复合物的位置，染色质可及性的变化以及由此产生的转录组变化， 影响细胞过程。总的来说，这一提议提供了巨大的潜力， 了解SWI/SNF生物学，并告知我们对表观遗传调控的理解，因为它涉及 免疫治疗反应。