Characterization of Immune-Related Alternative Polyadenylation Events in Cancer Immunotherapy

Abstract

Alternative polyadenylation (APA) is an important post-transcriptional modification commonly involved in tumor development. However, the functional roles of APA in tumor immunity remain largely unknown. Here, we performed an in-depth analysis of the 3’UTR usage of protein-coding genes and tumor immune response in 10,303 tumor samples across 31 cancer types to develop the immune-related APA event (ImmAPA) score pipeline, an integrated algorithm to characterize the regulatory landscape of APA events in cancer immunity-related pathways. Tumor-specific ImmAPAs that strongly correlate with immune cell infiltration and immune checkpoint blockade (ICB) treatment-related biomarkers were identified. Among these ImmAPAs, the top-ranking COL1A1 3’UTR usage was strongly associated with worse prognosis and tumor immune evasion. Furthermore, a machine learning approach to construct an ICB-related ImmAPA score model predicted immunotherapy efficacy. Overall, the characterization of immune-related APA that correspond to tumor progression and tumor immunity highlights the clinical utility of APA events as potential biomarkers in cancer immunotherapy.

The Transcriptional Landscape of Immune-Response 3′-UTR Alternative Polyadenylation in Melanoma

“…Increasing evidence has shown that APA events can be used as prognostic markers for cancer [ 5 , 18 , 19 , 20 , 21 ]. However, few reports have explored whether they can be used as potential biomarkers to predict the response of tumor patients to immunotherapy [ 22 ]. Herein, we proposed an in silico analysis pipeline.…”

“…APA, a pre-RNA processing mechanism widespread in all eukaryotes, is one of the major mechanisms of gene regulation [ 27 ]. APA has been reported to exhibit a quite good predictive power of prognosis [ 5 ], but thus far, regarding immunotherapy, only a small number of APA events were identified as immunotherapy responses of modulation [ 22 ].…”

“…We built a scoring system to predict immunotherapy response for patients according to Gaoyang Wang’s study [ 22 ]. Concretely, we initially screened out potential APA events related to immune-related pathways based on three gene sets (hallmark.all.…”

Pan-cancer landscape of immunology PIWI-interacting RNAs

“…Seventeen immune pathways were primarily collected on the basis of the ImmPort database [43] , which has been extensively applied in recent immunology studies [21] , [22] , [44] . All genes involved in these pathways were mapped to Ensembl IDs, and 1811 genes were adopted for subsequent analyses ( Table S1 ).…”

Versatile RNA: overlooked gems of the transcriptome

“…Since then, mounting evidence has shown this type of regulation to be tissue, developmental stage‐specific and part of normal gene regulation. There are many examples of altered lengths of 3′‐UTRs differentially targeted by trans‐factors such as microRNAs and RBPs [11–13]. Hence, currently, 3′‐UTRs are more visible given their critical roles [14,15].…”