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

探讨 ATP 依赖性染色质重塑复合物在免疫反应中的作用

基本信息

批准号：
10375502
负责人：
Dawn E Comstock
金额：
$ 5.18万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/10375502
关键词：
ARID1A gene 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 Gene Expression Profile Genes Genetic Genetic Screening 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 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

项目摘要

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 Desipte通过免疫疗法治疗癌症的明显临床成功，包括抗PD-1，抗CTLA-4 和抗PD-L1，大多数患者对这些疗法没有反应或初次复发回复。研究工作的研究旨在分析介导反应性的肿瘤细胞内在机制的作用免疫治疗为改善这些治疗策略提供了巨大的潜力。一层细胞尚待分析的固有调节是肿瘤细胞的表观遗传特征，以及如何调节水平会影响对免疫疗法的总体反应。表观遗传调节可以是通过染色质的结构重塑，通过哺乳动物等不同的复合物来实现开关/蔗糖不可发酵（MSWI/SNF）ATP依赖性染色质重塑复合物。 MSWI/SNF 利用来自ATP - 水解产生的能量来通过许多机制来改变染色质，包括射血核小体的不稳定和重组，允许改变不同遗传的可及性导致特定于高度调节基因表达的区域。 MSWI/SNF综合体特别兴趣是因为来自B16黑色素瘤中体内CRISPR屏幕的数据表明基因缺失编码MSWI/SNF的精选亚基每个赋予抗PD-1处理的抗性（Manguso等人， 2017）。通过该建议，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免疫疗法的反应性方面的作用，并深入询问通过分析基因组，MSWI/SNF，BAF和PBAF的构象在黑色素瘤中的机械作用这些复合物的位置，染色质访问的变化以及由此产生的转录组变化影响细胞过程。总体而言，该提案为影响基本的巨大潜力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节的理解免疫疗法的反应能力。