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. 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