Characterization of Immune-Related Alternative Polyadenylation Events in Cancer Immunotherapy.

Unlabelled: Alternative polyadenylation (APA) is an important posttranscriptional 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 corresponds to tumor progression and tumor immunity highlights the clinical utility of APA events as potential biomarkers in cancer immunotherapy.

Significance: Elucidation of the landscape of immune-related alternative polyadenylation in cancer identifies alternative polyadenylation events that may play a role in immune modulation and immunotherapy efficacy.