Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC

Abstract

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-γ 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.

Immune‐related long noncoding RNA signature for predicting survival and immune checkpoint blockade in hepatocellular carcinoma

“…Especially, emerging evidence suggests that lncRNAs act as regulators in controlling cancer immunity (Denaro et al, 2019). For instance, lncRNA-TIM-3 is shown to be associated with compromised antitumor immunity in HCC (Ji et al, 2018). Recently, studies suggest that immune-related lncRNAs may serve as new therapeutic targets and disease molecular F I G U R E 4 Several cancer hallmarks and immunologic characteristics regulated via the immune-related lncRNA signature.…”

Long Non-coding RNAs: Emerging Roles in the Immunosuppressive Tumor Microenvironment

“…TIM-3 expressed on the CD8 + T lymphocytes is reported to be correlated with the phenotype of immune exhaustion. Lnc-Tim3 lncRNA specifically blocked the interaction between TIM-3 and Bat3 by binding to the intracellular domain of TIM-3, which suppressed the downstream signaling of the Lck/NFAT1/AP-1 pathway (63). In vitro experiments indicated that Lnc-Tim3 inhibited the production of IFN-γ and IL-2 in CD8 + T lymphocytes, and enhanced the expression of antiapoptotic genes, such as Bcl-2 and MDM2.…”

Molecular and clinical characterization of Galectin‐9 in glioma through 1,027 samples

“…T-cell immunoglobulin mucin 3 (TIM3) as a Th1-specific cell surface protein can mediate macrophage activation, inhibit Th1mediated immune responses, and promote immune tolerance (Sakuishi et al, 2013). Blocking TIM3 can inhibit tumor growth by enhancing antitumor immunity to diseases such as prostate cancer and hepatocellular carcinoma (HCC; Das, Zhu, & Kuchroo, 2017;Ji et al, 2018;Wu et al, 2017). Gal9 binds to TIM3 to induce Th1 cells death (Zhu et al, 2005).…”