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Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Author

Listed:
  • 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
    Division of Pediatric Urology)

  • 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
    Center for Autoimmune Genomics and Etiology, CCHMC
    Division of Biomedical Informatics, 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
    Division of Pediatric Urology)

  • Edith M. Janssen

    (Division of Immunobiology, CCHMC)

  • Kakajan Komurov

    (Cincinnati Children’s Hospital Medical Center (CCHMC)
    Division of Biomedical Informatics, CCHMC
    Division of Human Genetics, CCHMC)

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.

Suggested Citation

  • 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 & Gan, 2018. "Defective transcription elongation in a subset of cancers confers immunotherapy resistance," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06810-0
    DOI: 10.1038/s41467-018-06810-0
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