Epigenetic therapy activates TE-chimeric transcripts to provide additional source of antigens in glioblastoma stem cells

ABSTRACT: Cancer-specific coding mutations can create neoantigens that can be presented on the cell surface of tumors to trigger immunogenic clearance1–4. However, current cancer vaccine approaches have not been universally effective5; this is especially true in tumors with a low mutational burden which, in turn, carry a low conventional neoantigen load6. Transposable elements (TEs) make up approximately 50% of the human genome and have been discovered to provide cryptic promoters, which can be reactivated with epigenetic manipulations to generate TE-gene chimeric transcripts that can be translated into noncanonical peptides7. Here, we focus on glioblastoma, an aggressive brain cancer with low mutation burden, to explore whether epigenetic therapy can induce TE-chimeric antigens (TEAs) to appreciably increase the antigen repertoire that can be targeted with immunotherapy. We perform comprehensive epigenetic and transcriptomic profiling of three patient-derived glioblastoma stem cell lines (GSCs) and, more importantly, astrocyte and fibroblast primary cell lines that are either proliferating or quiescent, treated with epigenetic therapy drugs to identify treatment-induced TEA (TI-TEA) candidates that are preferentially expressed in cancer cells. Although we verify TI-TEAs are indeed presented on HLA molecules in GSCs thus are promising cancer vaccine candidates, many TEs were also transcriptionally activated in proliferating primary cell lines after epigenetic therapy. This work presents a cautionary but optimistic tale for future efforts in harnessing TI-TEAs for targeted immunotherapy approaches.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Ju Heon Maeng  

LAB HEAD: Ting Wang

PROVIDER: PXD039893 | Pride | 2024-06-05

REPOSITORIES: Pride