1. Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus
- Author
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Marco Mineo, Paul A. Anderson, Khalid Shah, David A. Reardon, Sophia Auduong, Hiroshi Nakashima, Sean E. Lawler, Jasneet Kaur Khalsa, Rameen Beroukhim, William Y. Fan, Shawn M. Lyons, Carmela Passaro, Pavel Ivanov, Alexandra M Giantini Larsen, Keith L. Ligon, Quazim A. Alayo, E. Antonio Chiocca, Mykola Zdioruk, Niklas von Spreckelsen, Prakash Kharel, Ruben Ferrer-Luna, Hirotaka Ito, and Korneel Grauwet
- Subjects
Male ,Biology ,Primary transcript ,Immunotherapy, Adoptive ,Article ,B7-H1 Antigen ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Interferon ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gene silencing ,Molecular Biology ,Gene ,Aged ,030304 developmental biology ,Ribonucleoprotein ,0303 health sciences ,Gene knockdown ,RNA ,Cell Biology ,Janus Kinase 2 ,Middle Aged ,Programmed Cell Death 1 Ligand 2 Protein ,Gene Expression Regulation, Neoplastic ,Immunosurveillance ,STAT1 Transcription Factor ,Cancer research ,Female ,RNA, Long Noncoding ,Immunotherapy ,Interferons ,030217 neurology & neurosurgery ,Signal Transduction ,T-Lymphocytes, Cytotoxic ,medicine.drug - Abstract
Tumor interferon signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the interferon- (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. INCR1’s primary transcript binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2 enabling their expression. Together, these findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.
- Published
- 2020
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