Hyperactive Alternative RNA Splicing Facilitates Immune Escape in Small Cell Lung Cancer [RNA-Seq]

The mechanisms driving cancer immune escape remain incompletely understood. In this study, we reveal that alternative RNA splicing is hyperactivated in small cell lung cancer (SCLC), particularly in the classic neuroendocrine subtypes, and is associated with poor prognosis. ASCL1, a defining transcription factor of SCLC, directly binds to and upregulates the expression of most splicing factors, including PRMT5. Elevated levels of these splicing factors correlate with an increase in skipped exon (SE) and mutually exclusive exon (MXE) events. Notably, the skipped exons in SCLC exhibit strong immunogenicity and are associated with immune suppression. Genetic or pharmacological inhibition of PRMT5 significantly suppresses SCLC progression both in vitro and in vivo. Transcriptome analyses demonstrate that PRMT5 deficiency reduces the prevalence of SEs and MXEs and thus maintains exons with high immunogenicity. Consistent with these findings, GSK3368715, a clinically safe PRMT5 inhibitor, synergizes with anti-PD1 antibody to treat SCLC by repressing alternative RNA splicing and enhancing immune responses. Taken together, we propose that hyperactive alternative RNA splicing, which excludes exons with strong immunogenicity, serves as a key mechanism for immune escape in SCLC, which highlights a potential therapeutic vulnerability for this aggressive disease. Overall design: Bulk RNAseq in mouse normal lung organoids, SCLC organoids and SCLC organoids treated with GSK.