Neoepitope formation through the generation of RNA-derived “editopes”

Abstract

ABSTRACTTreatment-resistant tumors are frequently characterized by a low tumor mutational burden (TMB) and poor T-cell infiltration into the tumor microenvironment. Conversely, good responses to immunotherapy have been associated with high TMB and T-cell infiltration. This may imply that at least a subset of mutations in TMB-high tumors result in the generation of neoepitopes that are recognized (and cleared) by T cells. Currently, methods that specifically mutate MHC-presented tumor epitopes, while preserving genomic integrity, do not exist. Here, we have employed site-directed RNA editing to specifically alter MHC-presented tumor epitopes at the transcript level, with no modification to the genomic DNA, to modulate their antigenicity and recognition by cognate T-cell receptors (TCR). We demonstrate that RNA editing can be employed as a precision tool to specifically modulate antigenicity through the formation of RNA editing derived neoepitopes, which we have termed “editopes”. In particular, we show potent induction of a T-cell response to an optimally edited peptide (40%) compared to a non-immunogenic mutant peptide (<2%) and its WT counterpart (20%). This study shows the potential of RNA editing as a method to improve tumor recognition by T cells and to favor tumor clearance.