Teaching T cells to see transcriptional dysregulation : TCR-T and cancer vaccines in Ewing sarcoma

Abtract : Every case of Ewing sarcoma is driven by an oncogenic chimeric transcription factor, most commonly EWSR1::FLI1.  In addition to causing quantitative misregulation of expression levels for many genes throughout the genome, we have shown that these oncogenic fusions also drive the expression of cryptic germline encoded gene-like sequences usually silenced in normal tissues, which we term neogenes.  A subset of these neogenes are also translated and encode peptides presented by HLA complexes on the tumor call surface.  These results are now being translated into the clinic through both TCR-T adoptive cell therapy and mRNA LNP therapeutic vaccines.