Abstract 5719: RNA-based tumor neoantigens from intron retention

Abstract

Abstract Background: Tumor neoantigens contribute to cancer immunity and may influence selective immune checkpoint inhibitor response. Translation of nonsynonymous somatic mutations in tumor cells generates mutant peptides that can be recognized as foreign by the host immune system. Alterations in tumor RNA, rather than DNA, may also contribute to the tumor neoantigen landscape. Intron retention, a widespread feature of cancer transcriptomes, represents a novel source of tumor neoantigens. Methods: We developed an in silico pipeline leveraging existing tools and novel methods to computationally identify retained-intron neoantigens (RI-neoantigens) from transcriptome sequencing data. We applied our computational pipeline to three cohorts of melanoma patients (n = 89) treated with immune checkpoint blockade. Results: This approach identified a mean RI-neoantigen burden of 3,643 across cohorts, which augments the mean DNA-derived somatic neoantigen burden by roughly 4.5-fold. 3,253 RI-neoantigens were exclusively present in two or more patients who responded to immunotherapy. A subset of responder-exclusive RI-neoantigens were validated by peptide restimulation assay. A candidate RI-neoantigen from a cancer cell line was identified in complex with MHC I by mass spectrometry, supporting the hypothesis that aberrant splicing results in intron retention, which generates abnormal transcripts that are translated into immunogenic peptides and presented to the immune system. Conclusions: Our results demonstrate the contribution of transcriptional dysregulation to the overall burden of tumor neoantigens. Further study of RI-neoantigens may expand our understanding of tumor immunity and identify immunogenic peptide sequences for personalized cancer vaccines. Citation Format: Claire A. Margolis, Alicia C. Smart, Dennis Adeegbe, Diana Miao, Meng Xiao He, Harold Pimentel, Tim Fugmann, Kwok-Kin Wong, Eliezer M. Van Allen. RNA-based tumor neoantigens from intron retention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5719.