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

Chuanpeng Dong,Christina Y Yu,Yunlong Liu,Jill L Reiter,Mohammad Abu Zaid,Yue Wang,Giuseppe Bombaci,Brian A Walker,Xiongbin Lu,Zhaoyang Jiang,Fabiana Perna,Annamaria Cesarano,Kun Huang

doi:10.1038/s41388-021-02005-y

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.

Highlights

Multiple Myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow [1]
6131 RESULTS Genes involved in spliceosome activities are differentially expressed between MM and normal plasma cells To investigate whether the expression of genes involved in RNA splicing was altered in MM compared to normal plasma cells, we analyzed differentially expressed genes using RNA-seq data of plasma cells from five newly diagnosed MM patients (NDMM) and five healthy controls (GSE110486)
We found that the 230 upregulated differentially expressed genes identified in GSE110486 were highly enriched in the NDMM samples from the MMRF cohort, as compared to the normal plasma cells (Fig. S1A)

Summary

Introduction

Multiple Myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow [1]. Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many solid tumors by harnessing the immune system for effective anticancer treatment [3]. In these diseases, clinical response to ICB therapy is associated with the presence of tumor-specific antigenic peptides, or neoantigens [4], a source of potential neoepitopes that can be loaded onto major histocompatibility complex (MHC) class I molecules to generate an antitumor immune response [5]. In contrast to solid tumors, mutation-derived neoantigen load in MM has been associated with unfavorable outcome [11, 12]

Methods

Results

Conclusion