Paper Reading
01
The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion
Jiang, R., Tang, J., Chen, Y.et al.
Nat Commun8,15129 ()
Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma(HCC). Here, the author elucidates the impact of lncRNAs in linking Tregs and HCC. Firstly, the author shows that EGFR upregulation in Tregscorrelates positively with the tumor size and expression of EGFR/Foxp3, but negatively with IFN-g expression in patients and xenografted mouse models. Then they found that Inc-EGFR stimulates Tregdifferentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. In summary, the paper has discovered a novel lncRNA-lnc-EGFR, which links Tregs and HCC. Inc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potentialtherapeutic target for HCC.
DOI:10.1038/ncomms15129
02
Translation control of the immune checkpoint in cancer and its therapeutic targeting
Xu, Y., Poggio, M., Jin, H.Y.et al.
Nat Med25,301–311 ()
Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, the author develops an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. Firstly, the author shows that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in the translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Then, the analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. In conclusion, the paper shows that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg; KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.DOI:10.1038/s41591-018-0321-2
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