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Updated: Jan 30, 2026
Working with Human Tissues for Translational Cancer Research
Published on: November 26, 2015
Translation control of the immune checkpoint in cancer and its therapeutic targeting
Yichen Xu1,2, Mauro Poggio1,2, Hyun Yong Jin1,2
1Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
Abstract:
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, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show 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 translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further 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. We show 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.
Insights
MYC and KRAS oncogenes cooperate in liver cancer to suppress immune responses by altering programmed-death-ligand 1 (PD-L1) translation. Targeting this mechanism with eFT508 reverses tumor aggression and metastasis.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer cells evade immune surveillance by modulating messenger RNA expression.
- The precise molecular mechanisms by which cancer cells achieve this remain largely unknown.
Purpose of the Study:
- To investigate oncogene cooperation in liver cancer immunosurveillance using a novel mouse model.
- To elucidate the molecular mechanisms of immune evasion driven by MYC and KRAS.
Main Methods:
- Development of a MYC-overexpressing (MYCTg) and KRASG12D-mutated liver cancer mouse model.
- Genome-wide ribosomal footprinting to analyze mRNA translation alterations.
- Investigated the role of upstream open reading frames in PD-L1 translation regulation.
- Tested the efficacy of eIF4E phosphorylation inhibitor eFT508 in reversing tumor characteristics.
Main Results:
- MYCTg synergized with KRASG12D to induce aggressive liver tumors, metastasis, and reduced survival.
- PD-L1 translation was repressed in KRASG12D tumors via 5' untranslated region elements, a mechanism bypassed in MYCTg;KRASG12D tumors.
- eFT508 treatment reversed aggressive and metastatic phenotypes in MYCTg;KRASG12D tumors by upregulating PD-L1 translation.
Conclusions:
- Distinct oncogenes manipulate immune-checkpoint protein translation to promote immune evasion.
- This translational control mechanism of PD-L1 offers a novel therapeutic target for liver cancer immunotherapy.
- Targeting eIF4E phosphorylation with compounds like eFT508 shows promise for treating aggressive, metastatic liver cancers.
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