期刊
MOLECULAR CELL
卷 78, 期 6, 页码 1207-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.05.015
关键词
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资金
- NIH [2P01CA163205, CA069246-20, K99GM124458, R01GM126150, R35GM126901]
- Brigham Research Institute microgrant
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Research Fellowship [400975596]
- American Brain Tumor Association Basic Research Fellowship
- Howard Hughes Medical Institute Medical Research Fellow Program
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.
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