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

• 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
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.05.015

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.