Mineo, Marco, Lyons, Shawn M., Zdioruk, Mykola, von Spreckelsen, Niklas ORCID: 0000-0002-9873-1711, Ferrer-Luna, Ruben, Ito, Hirotaka ORCID: 0000-0001-8223-0229, Alayo, Quazim A., Kharel, Prakash, Larsen, Alexandra Giantini, Fan, William Y., Auduong, Sophia, Grauwet, Korneel, Passaro, Carmela, Khalsa, Jasneet K., Shah, Khalid, Reardon, David A., Ligon, Keith L., Beroukhim, Rameen, Nakashima, Hiroshi, Ivanov, Pavel ORCID: 0000-0002-7986-7760, Anderson, Paul J., Lawler, Sean E. and Chiocca, E. Antonio (2020). Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus. Mol. Cell, 78 (6). S. 1207 - 1232. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFN gamma signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFN gamma-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFN gamma signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mineo, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lyons, Shawn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zdioruk, MykolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Spreckelsen, NiklasUNSPECIFIEDorcid.org/0000-0002-9873-1711UNSPECIFIED
Ferrer-Luna, RubenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ito, HirotakaUNSPECIFIEDorcid.org/0000-0001-8223-0229UNSPECIFIED
Alayo, Quazim A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kharel, PrakashUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larsen, Alexandra GiantiniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fan, William Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auduong, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grauwet, KorneelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Passaro, CarmelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khalsa, Jasneet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, KhalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reardon, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ligon, Keith L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beroukhim, RameenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakashima, HiroshiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ivanov, PavelUNSPECIFIEDorcid.org/0000-0002-7986-7760UNSPECIFIED
Anderson, Paul J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lawler, Sean E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiocca, E. AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-329598
DOI: 10.1016/j.molcel.2020.05.015
Journal or Publication Title: Mol. Cell
Volume: 78
Number: 6
Page Range: S. 1207 - 1232
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4164
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LONG NONCODING RNA; CHIMERIC ANTIGEN RECEPTOR; IMMUNE CHECKPOINT BLOCKADE; T-CELLS; CANCER-CELLS; EXPRESSION; GAMMA; EVOLUTION; GLIOMA; IMMUNOTHERAPYMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32959

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