TY - JOUR
T1 - Defective transcription elongation in a subset of cancers confers immunotherapy resistance
AU - Modur, Vishnu
AU - Singh, Navneet
AU - Mohanty, Vakul
AU - Chung, Eunah
AU - Muhammad, Belal
AU - Choi, Kwangmin
AU - Chen, Xiaoting
AU - Chetal, Kashish
AU - Ratner, Nancy
AU - Salomonis, Nathan
AU - Weirauch, Matthew T.
AU - Waltz, Susan
AU - Huang, Gang
AU - Privette-Vinnedge, Lisa
AU - Park, Joo Seop
AU - Janssen, Edith M.
AU - Komurov, Kakajan
N1 - Funding Information:
This work was in part supported by NCI (CA193549) and CCHMC Research Innovation Pilot awards to KK, and Department of Defense (BC150484) award to NS. The genomic sequencing core at the University of Cincinnati is supported by P30-ES006096.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06810-0
DO - 10.1038/s41467-018-06810-0
M3 - Article
C2 - 30353012
AN - SCOPUS:85055462044
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4410
ER -