Defective transcription elongation in a subset of cancers confers immunotherapy resistance.

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Defective transcription elongation in a subset of cancers confers immunotherapy resistance.

Nat Commun. 2018 10 23;9(1):4410

Authors: Modur V, Singh N, Mohanty V, Chung E, Muhammad B, Choi K, Chen X, Chetal K, Ratner N, Salomonis N, Weirauch MT, Waltz S, Huang G, Privette-Vinnedge L, Park JS, Janssen EM, Komurov K

Abstract
The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TEdeff tumors. Remarkably, TEdeff correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TEdeff in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.

PMID: 30353012 [PubMed - indexed for MEDLINE]

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