Translation control of the immune checkpoint in cancer and its therapeutic targeting
Open accessAbstract
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 (MYC Tg) synergizes with KRAS G12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRAS G12D alone. Genome-wide ribosomal footprinting of MYC Tg;KRAS G12 tumors compared with KRAS G12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRAS G12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYC Tg;KRAS G12D 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 MYC Tg;KRAS G12D 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.
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MYC overexpression leads to PD-L1 overexpression, while TP53 mutations promote recruitment of immunosuppressive cells.
“MYC overexpression leads to PD-L1 overexpression, whereas TP53 mutations promote the recruitment of immunosuppressive cells75.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [75]
The Results section ('MYC reprograms PD-L1 expression at the translation level'; page unavailable) reports increased PD-L1 protein in MYC-expressing, KRAS-mutant liver tumors. The paper does not support the claim that TP53 mutations recruit immunosuppressive cells: its immune-cell findings concern MYC and KRAS, not TP53. (LLM, conf=0.90)
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References 72 · Cited by 261
Research works printed but not linked: 1
- [4]Stewart BW & Wild C World Cancer Report 2014 (International Agency for Research on Cancer WHO Press, 2014). 39432694
- Authors
- Xu, Y., Poggio, M., Jin, H. Y., Shi, Z., Forester, C. M., Wang, Y., Stumpf, C. R., Xue, L., Devericks, E., So, L., Nguyen, H. G., Griselin, A., Gordan, J. D., Umetsu, S. E., Reich, S. H., Worland, S. T., Asthana, S., Barna, M., Webster, K. R., Cunningham, J. T., & Ruggero, D.
- Affiliations
- University of California, San Francisco (US)
- Stanford University (US)
- eFFECTOR Therapeutics (United States) (US)
- Corresponding author
- Ruggero, Davide
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-01-14
- Volume
- 25
- Issue
- 2
- Pages
- 301-311
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6613562
- OpenAlex
- W2908902954
- Cited by
- 261
- References
- 72
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 36 · 2023: 48 · 2022: 39 · 2021: 37 · 2020: 36 · 2019: 17
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5k12hd072222-05)
- National Cancer Institute (R01CA140456, R01CA184624, T32CA128583, R01CA154916)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD072222, R01HD086634)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- immune checkpoint, PD-L1, mRNA translation, oncogene cooperation, c-Myc, KRAS G12D, liver cancer, metastasis, immune evasion, ribosome profiling, upstream open reading frames, eIF4E phosphorylation, immunotherapy, tumor surveillance
- MeSH terms
- Animals, Base Sequence, Immunotherapy, Liver Neoplasms, Mice, Inbred C57BL, Neoplasm Metastasis, Pyridines, Pyrimidines, Transcription, Genetic, Protein Biosynthesis, Down-Regulation, Up-Regulation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Open Reading Frames, Disease Progression, 5' Untranslated Regions, Eukaryotic Initiation Factor-4E, Kaplan-Meier Estimate, Immune Evasion, Tumor Microenvironment, B7-H1 Antigen
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