Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus

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 IFNγ signaling in multiple tumor types. Si...

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Bibliographic Details
Published in:Molecular cell 2020-06, Vol.78 (6), p.1207-1223.e8
Main Authors: Mineo, Marco, Lyons, Shawn M., Zdioruk, Mykola, von Spreckelsen, Niklas, Ferrer-Luna, Ruben, Ito, Hirotaka, Alayo, Quazim A., Kharel, Prakash, Giantini Larsen, Alexandra, 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, Anderson, Paul J., Lawler, Sean E., Chiocca, E. Antonio
Format: Article
Language:English
Subjects:
Aged
Animals
B7-H1 Antigen - genetics
cancer
CAR T cell therapy
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic - drug effects
HNRNPH1
Humans
Immunotherapy
Immunotherapy, Adoptive - methods
INCR1
interferon signaling
Interferon-gamma - genetics
Interferon-gamma - metabolism
Interferons - genetics
Interferons - metabolism
JAK2
Janus Kinase 2 - genetics
Janus Kinase 2 - metabolism
long noncoding RNA
Male
Mice
Mice, Inbred NOD
Middle Aged
PD-L1
Programmed Cell Death 1 Ligand 2 Protein - genetics
RNA, Long Noncoding - genetics
Signal Transduction - drug effects
STAT1 Transcription Factor - metabolism
T-Lymphocytes, Cytotoxic
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Summary: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 IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-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 IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy. [Display omitted] •INCR1 is expressed from the PD-L1 locus in interferon-stimulated tumor cells•INCR1 regulates tumor interferon signaling•Silencing INCR1 sensitizes tumor cells to T cell-mediated killing•INCR1 binds HNRNPH1 to promote PD-L1 and JAK2 expression Mineo et al. investigate the role of lncRNAs in tumor immune evasion. They show that INCR1, a lncRNA expressed in response to interferon stimulation, regulates the expression of several immunosuppressive molecules to promote tumor escape from T cell attack.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2020.05.015