| Literature DB >> 32504554 |
Marco Mineo1, Shawn M Lyons2, Mykola Zdioruk3, Niklas von Spreckelsen4, Ruben Ferrer-Luna5, Hirotaka Ito3, Quazim A Alayo3, Prakash Kharel6, Alexandra Giantini Larsen3, William Y Fan3, Sophia Auduong3, Korneel Grauwet3, Carmela Passaro3, Jasneet K Khalsa7, Khalid Shah7, David A Reardon8, Keith L Ligon9, Rameen Beroukhim10, Hiroshi Nakashima3, Pavel Ivanov11, Paul J Anderson11, Sean E Lawler3, E Antonio Chiocca12.
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 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.Entities:
Keywords: CAR T cell therapy; HNRNPH1; INCR1; JAK2; PD-L1; cancer; interferon signaling; long noncoding RNA
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Year: 2020 PMID： 32504554 PMCID： PMC7377926 DOI： 10.1016/j.molcel.2020.05.015
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970