Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0528-7
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Funding
- State Key Program of National Natural Science of China [81430062]
- National Basic Research Program of China [2012CB910800]
- Jiangsu Provincial Natural Science Foundation-Youth Foundation [BK20170699]
- National Natural Science Foundation of China [81702323]
- program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU
- Priority Academic Program of Jiangsu Higher Education Institutions
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Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-gamma and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.
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