[Aberrant RNA Splicing Regulation as a Novel Source of Neoantigens].

Abstract

During oncogenesis and proliferation of cancer cells, numerous alterations occur in genomic DNA and mRNA, and these alterations consequently result in the production and presentation of cancer-specific epitopes(neoantigens)on cancer cell surface through the major histocompatibility complex(MHC). These neoantigens then mark cancer cells as"non-self"leading to elimination by the immune system. One of the major insights from cancer genome studies is the detection of neoantigens. Some cancer genome mutations produce neoantigens, enhancing the responsiveness to immune checkpoint blockade (ICB)therapies. The tumor mutation burden(TMB)is used as a surrogate metric for the rate of neoantigen production, and practically used as a biomarker to determine suitability of pembrolizumab, an anti-PD-1 ICB. The focus of neoantigen analysis has been on mutations in genomic DNA. However, recent studies revealed cancer-specific mRNA arising from RNA splicing also provides a source of neoantigens. These findings would provide more detailed insights into cancer immune response and improve the predictive accuracy of ICB effects. In this article, recent progress about RNA splicing-associated neoantigens is summarized.