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 and Kakajan Komurov ()
Additional contact information
Vishnu Modur: Cincinnati Children’s Hospital Medical Center (CCHMC)
Navneet Singh: Cincinnati Children’s Hospital Medical Center (CCHMC)
Vakul Mohanty: University of Cincinnati Graduate Program in Systems Biology and Physiology
Eunah Chung: Division of Developmental Biology, CCHMC
Belal Muhammad: Cincinnati Children’s Hospital Medical Center (CCHMC)
Kwangmin Choi: Cincinnati Children’s Hospital Medical Center (CCHMC)
Xiaoting Chen: Center for Autoimmune Genomics and Etiology, CCHMC
Kashish Chetal: Division of Biomedical Informatics, CCHMC
Nancy Ratner: Cincinnati Children’s Hospital Medical Center (CCHMC)
Nathan Salomonis: Division of Biomedical Informatics, CCHMC
Matthew T. Weirauch: Division of Developmental Biology, CCHMC
Susan Waltz: University of Cincinnati and Cincinnati Veteran’s Hospital Medical Center
Gang Huang: Division of Pathology, CCHMC
Lisa Privette-Vinnedge: Division of Oncology, CCHMC
Joo-Seop Park: Division of Developmental Biology, CCHMC
Edith M. Janssen: Division of Immunobiology, CCHMC
Kakajan Komurov: Cincinnati Children’s Hospital Medical Center (CCHMC)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06810-0

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