Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Vishnu Modur, Navneet Singh, Vakul Mohanty, Eunah Chung, Belal Muhammad, Kwangmin Choi, Xiaoting Chen, Kashish Chetal, Nancy Ratner, Nathan Salomonis, Matthew T. Weirauch, Susan Waltz, Gang Huang, Lisa Privette-Vinnedge, Joo Seop Park, Edith M. Janssen, Kakajan Komurov

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Article number4410
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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