Retained Introns Can Produce Tumor-Specific Neoepitopes in Melanoma

Tumor-specific neoepitopes may be therapeutic targets in personalized cancer vaccines and immunotherapies. The targets can be neoepitopes generated by somatic mutations or aberrant peptides generated from germline antigens that are transcriptionally silenced in normal adult tissues. Cancer transcriptomes often contain aberrant mRNAs resulting from dysregulated splicing, a process which frequently results in intron retention. Transcripts with retained introns are translated and degraded by the nonsense-mediated decay pathway. This generates peptides that may be presented on the cell surface by MHC class I; however, it is not known if retained intron transcripts yield tumor-specific neoepitopes in cancer. Smart, Margolis, and colleagues developed a computational method to detect intron retention events using bulk RNA-sequencing (RNA-seq) data from tumors and identify putative retained intron neoepitopes. This in silico approach was applied to tumor RNA-seq data from two cohorts of patients with melanoma (48 patients total) treated with immune checkpoint inhibitors. The cohorts had comparable levels of intron retention and predicted retained intron neoepitopes. Across cohorts, mean total predicted neoepitope load, comprised of both somatic mutation neoepitopes and retained intron neoepitopes, was augmented roughly 0.7-fold with the addition of retained intron neoepitopes. Retained intron neoepitope load was not associated with response to immune checkpoint blockade. Mass spectrometry immunopeptidome analysis of multiple cancer cell lines determined that several predicted retained intron neoepitopes were processed and presented on MHC 1 on the surface of melanoma cells, validating these retained intron-derived peptides as tumor neoepitopes. Taken together, these findings suggest that intron retention from aberrant splicing can produce immunogenic peptides that are presented by MHC 1. Further, the computational method created to identify tumor-specific retained intron neoepitopes may aid in the development of personalized cancer vaccines.

Smart AC, Margolis CA, Pimentel H, He MX, Miao D, Adeegbe D, et al. Intron retention is a source of neoepitopes in cancer. Nat Biotechnol 2018 Aug 16 [Epub ahead of print].

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