Global loss of epigenetic and transcriptional fidility defines a subclass of cancer with immunotherapy resistance [RCC]

We report that some cancers have extensive loss of epigenetic and transcriptional fidelity, characterized widespread spurious transcription and mRNA processing defects (Loss of transcriptional fidelity: LTF+). LTF impairs transcriptional elongation and imposes a highly specific molecular phenotype where pathways regulated by long genes, such as those involved in inflammatory response are consistently impaired in LTF+ tumors. Accordingly LTF blunts inflammatory response and confers resistance to immune mediated anti-tumor attack, and correlates with poor response to immunotherapeutic drugs in renal cell carcinoma and melanoma patients. We show that genetic or chemical perturbation of gene body histone methylation or of transcriptional elongation can recapitulate LTF-like phenotype, imposing resistance to immune-mediated anti-tumor mechanisms in-vitro and in-vivo. Overall design: Paired end poly A selected RNAseq was performed on RNA extracted from 1-10 micro meter thickness OCT embedded renal clear cell carcinoma (RCC) tumors obtained from University of Cincinnati Tumor Bank. Expression profiling of these samples was used to identify LTF+ samples in an independent cohort.