27Characterization of aberrant alternative splicing landscape in patients with metastatic renal cell carcinoma

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Abstract Background Errors in alternative splicing (AS) events are recognized as contributors to the tumorigenesis and metastasis of various cancer types. However, the role of aberrant AS events in metastatic renal cell carcinoma (mRCC) remains largely unexplored. We aimed to identify aberrant AS events associated with clinical benefits from immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in mRCC. Methods We conducted a retrospective analysis on 101 patients with mRCC who received systemic therapy and underwent RNA sequencing with sufficient output quality. Patients were categorized into two cohorts based on whether they received ICIs or TTs. Patients were then further subcategorized as responders or non-responders to systemic therapy based on RECIST v1.1 criteria. Differential gene expression and splicing analyses were performed between responders and non-responders for each cohort. Paired-end bulk RNA sequencing, utilized in the analyses of splicing events, was performed as part of the OncoExTra clinical assay. Novel AS events were analyzed for their potential to generate peptide neoantigens through MHC class I binding predictions. Results Outlier splicing analysis identified 10 aberrant AS events specific to mRCC. Alternative splicing analysis revealed 409 differentially spliced events between responders and non-responders in the ICI cohort and 231 in the TT cohort, with intron retention enriched as the predominant motif of aberrant AS in responders relative to non-responders. Seven unique AS events were enriched in responders, including PTPN6, ACTN1, and SUN2. Predictive neoantigen analysis identified high MHC class I binding potential in peptides from AS events in IFFO1, ZNF692, and SUN2. A novel splice burden gene set was developed from differentially expressed genes in novel splice burden-high samples. Within both ICI and TT cohorts, this splice burden-high gene set was enriched in responders relative to non-responders. The presence of high splice burden was linked to an immunogenic tumor microenvironment, characterized by enriched antigen processing and adaptive immune responses. Nearly 50 adaptive immune cell pathways were enriched in splice burden-high patients, including CD22-mediated BCR regulation, immunoglobulin production, and humoral immune response. Conclusions This study provides a comprehensive analysis of AS events in mRCC, highlighting enrichment of intron retention as potential transcriptomic biomarkers for treatment response. Numerous adaptive immune gene pathways were enriched in mRCC patients with high splice burden, particularly humoral immune responses. Aberrant AS-derived neoantigens may serve as potential targets for adoptive cell therapy strategies.

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