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

• 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
• 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

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