Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma

Abstract

Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes. MM-specific IR events were identified in RNA-sequencing data from the Multiple Myeloma Research Foundation CoMMpass study after removing IR events that also occurred in normal plasma cells. We quantified the IR-neoAg load by assessing IR-induced novel peptides that were predicted to bind to major histocompatibility complex (MHC) molecules. We found that high IR-neoAg load was associated with poor overall survival in both newly diagnosed and relapsed MM patients. Further analyses revealed that poor outcome in MM patients with high IR-neoAg load was associated with high expression levels of T-cell co-inhibitory molecules and elevated interferon signaling activity. We also found that MM cells exhibiting high IR levels had lower MHC-II protein abundance and treatment of MM cells with a spliceosome inhibitor resulted in increased MHC-I protein abundance. Our findings suggest that IR-neoAg may represent a novel biomarker of MM patient clinical outcome and further that targeting RNA splicing may serve as a potential therapeutic strategy to prevent MM immune escape and promote response to checkpoint blockade.

Bioinformatics detection of modulators controlling splicing factor‐dependent intron retention in the human brain

“…Type 1 diabetes is an evolving field of interest where splicing alterations can unveil novel immunogenic epitopes (Wu et al, 2021). In addition, IR is a frequent event in many cancer types, and our recent studies have shown that IR-induced neoantigens may be a useful biomarker for predicting survival in multiple myeloma and pancreatic cancer patients (Dong et al, 2021(Dong et al, , 2022.…”

A unified model for the surveillance of translation in diverse noncoding sequences

“…Recently, recurrent stop codon mutations leading to readthrough into 3’ UTRs have been detected in over 400 cancer-related genes (Dhamija et al, 2020). Further supporting elevated noncanonical ORF translation in cancer, peptides derived from noncoding regions account for the majority of tumor-specific antigens (Laumont et al, 2018; Smart et al, 2018; Xiang et al, 2021), and tend to be associated with unfavorable prognoses for patients (Dong et al, 2021). Similarly, increased intron retention and other aberrant splicing events are associated with aging and neurodegeneration (Adusumalli et al, 2019; Hsieh et al, 2019; Mariotti et al, 2022; Mazin et al, 2013).…”

Retained introns in long RNA-seq reads are not reliably detected in sample-matched short reads

“…While an improvement, our intron persistence metric only partially accounts for admixed splicing patterns from different cell types in a mixed-cell sample such as HX1. Like other RI detection studies [15–17, 25, 31, 34, 43], our approach is explicitly linked to annotation (here, GENCODE v35) and therefore reports IR only relative to annotated transcripts, ignoring potential unannotated transcripts. We also did not explore the entanglement of biological and technical effects in the length of persistent introns: shorter introns are more likely to be retained [43, 55, 56], but the length limit of PacBio Iso-Seq reads of up to 10 kilobases means that any molecules with longer persistent introns were not considered in this study.…”