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.
Cancer immunotherapy treatments have shown marked efficacy across a range of cancer types; however, many patients still do not respond to these treatments or initially respond but later relapse. Understanding the factors and cellular processes that impact responsiveness to immunotherapies will be essential to improving therapeutic strategies to treat patients. The investigations proposed under this F30 proposal aim to identify and mechanistically characterize epigenetic factors, specifically, ATP-dependent chromatin remodeling complexes, which modulate response to immunotherapy-based agents in efforts to define predictive biomarkers and provide the foundation for new complementary therapeutic strategies.
