Defective transcription elongation in a subset of cancers confers immunotherapy resistance (B16 RNA-Seq). Defective transcription elongation in a subset of cancers confers immunotherapy resistance (B16 RNA-Seq)

The nature and the role of global transcriptional deregulations in cancers are not fully understood. We report a phenotype in a significant portion of cancers characterized by widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) were characterized by spurious transcription and defective mRNA processing, specifically in a large set of genes characterized by long genomic length, poised promoters and inducible expression. As such, signaling pathways regulated by such genes, such as interferon/JAK/STAT and TNF/NF-κB pathways, were consistently suppressed in TEdeff tumors. Remarkably, TEdeff significantly correlated with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients in 4 different cohorts. Importantly, forced pharmacologic or genetic induction of TEdeff in tumor cells impaired the expression of the interferon/JAK/STAT and TNF/NF-κB pathways, and imposed resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a novel epigenetic mechanism in the tumor arsenal of immune resistance tools, which warrants its assessment in cancer patients undergoing immunotherapy. Overall design: RNAseq was used to profile expression patterns in human (cancer cell lines and tumor tissues) and flavopiridol,a CDK9 inhibitor, treated mouse B16-F10 cell lines to identify and characterize Tedeff cancers. We also performed RNApol2 and RNApol2-ser5 chipseq to study the genome wide distribution of RNA polymerase 2 in TEdeff canmcer cell lines vs control cancer cell lines