Translation control of the immune checkpoint in cancer and its therapeutic targeting

Nat Med. 2019 Feb;25(2):301-311. doi: 10.1038/s41591-018-0321-2. Epub 2019 Jan 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Animals
  • B7-H1 Antigen / metabolism
  • Base Sequence
  • Disease Progression
  • Down-Regulation
  • Eukaryotic Initiation Factor-4E / metabolism
  • Gene Expression Regulation, Neoplastic
  • Immune Evasion
  • Immunotherapy*
  • Kaplan-Meier Estimate
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy*
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Open Reading Frames / genetics
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Transcription, Genetic
  • Tumor Microenvironment
  • Up-Regulation / genetics


  • 5' Untranslated Regions
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Pyrimidines
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • tomivosertib