I am a student in the MSTP (MD-PhD) program at Washington University School of Medicine in St. Louis, pursuing my thesis in the lab of Dr. Ting Wang. My research passion is understanding the role of transposable elements (TEs) in cancer. These remnants of ancient viruses, which have incorporated into our genomes over hundreds of millions of years of evolution, account for approximately 50% of genomic DNA content, but until now their contribution to various disease processes has remained unexplored. My research will provide deeper insight into the gene regulatory aberrations that determine the cancer cell phenotype and may illuminate previously unknown molecular
targets in precision cancer therapy.
Noah Basria, Josh Jangb, Nakul Shaha, Holden Lianga, Ting Wanga
aWashington University School of Medicine, St. Louis, MO, USA; bVAI, Grand Rapids, MI, USA
Among the CNS neoplasms, glioblastoma (GBM) is the most common and most lethal. Profiling the GBM histologic, genetic and epigenetic landscapes enables clinical stratification of distinct patient populations with prognostic and therapeutic implications. Despite accounting for nearly half the genome content, transposable elements (TEs) have been underexplored in cancer genomic studies owing to their constitutive epigenetic repression in somatic cells. However, clinical application of DNA methyltransferase (DNMTi) and histone deacetylase inhibitors (HDACi) have demonstrated potent activation of TE-derived alternative transcriptional start sites. Here, we show that decitabine (DNMTi) and panobinostat (HDACi) work both alone and synergistically to increase TE-expression by reversing their epigenetic repression in glioblastoma stem cells (GSCs). When translated, transcripts initiated at cryptic TE-derived alternative transcription start sites are processed and presented on cell surface HLA-I, potentially enabling immunotherapy targeting of these tumor-specific antigens.
Specifically, we performed epigenomic and transcriptomic profiling of three patient-derived GSC lines, quiescent and replicating fibroblast and normal human astrocyte controls treated with 1uM decitabine DNMTi and 100nM panobinostat HDACi. In silico immunogenomics tools were then applied to assess the antigenicity of translated TE-derived transcripts. Finally, HLA-I peptidome immunoprecipitation, followed by liquid chromatography tandem mass-spectrometry (LC-MS/MS) were used to validate TE-derived peptides at the proteomic level. Beyond corroborating previously observed cryptic TE-promoter activation by DNMTi and HDACi, we demonstrate immunopeptidomic changes in epigenetic therapy-treated GSCs and posit the potential synergistic value of epigenetic therapy in immuno-oncology treatment regimens.