Defective transcription elongation in a subset of cancers confers immunotherapy resistance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30353012.
- Also identified by DOI 10.1038/s41467-018-06810-0 and PMC identifier 6199328.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (TE<sup>deff</sup>) 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 TE<sup>deff</sup> tumors. Remarkably, TE<sup>deff</sup> 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 TE<sup>deff</sup> 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.
Medical subject headings
- Immunotherapy
- Neoplasms
- Transcription Elongation, Genetic