The spliceosome pathway activity correlates with reduced anti-tumor immunity and immunotherapy response, and unfavorable clinical outcomes in pan-cancer

Abstract

Alterations in the spliceosome pathway (SP) have been associated with diverse human cancers. In this study, we explored associations of the SP activity with various clinical features, anti-tumor immune signatures, tumor immunity-related genomic and molecular features, and the response to immunotherapies and targeted therapies in 29 cancer types from The Cancer Genome Atlas (TCGA) database. We showed that the SP activity was an oncogenic signature, as evidenced by its hyperactivation in cancer and invasive cancer subtypes and correlations with unfavorable clinical outcomes and anti-tumor immunosuppression in various cancers. The SP activity showed positive correlations with tumor mutation burden (TMB) and aneuploidy in diverse cancers, suggesting its association with genomic instability. However, the negative association between the SP activity and anti-tumor immune response was independent of its associations with aneuploidy and TMB. Furthermore, we supported that the SP activity had a negative correlation with immunotherapy response in four cancer cohorts treated by immune checkpoint inhibitors. Moreover, elevated SP activity is correlated with increased drug sensitivity for a broad spectrum of anti-tumor targeted therapies. In conclusion, the SP activity is a negative biomarker for anti-tumor immune response, prognosis, and the response to immunotherapeutic and targeted drugs in pan-cancer.