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CTG-Initiated Cryptic Peptide Translation Up- and Downstream of a Canonical ATG Start Codon Is Enhanced by TLR

Ziye Song1, Youkyung Lim1, Anneloes van Krimpen2

  • 1Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Cancer Immunology Research
|June 3, 2025
PubMed

Insights

Noncanonical translation can create cryptic antigens from alternative start codons, enhancing cancer immunotherapy. This study shows cryptic antigen expression is position-independent and effectively targets tumors, delaying progression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • Cytotoxic T lymphocytes (CTLs) recognize viral or tumor peptides on MHC class I molecules.
  • Noncanonical translation, initiated at noncanonical start codons, produces cryptic polypeptides.
  • Cryptic polypeptides are presented on MHC class I and are potential cancer immunotherapy targets.

Purpose of the Study:

  • To investigate the impact of the relative localization of a CTG-initiated open reading frame (ORF) to a canonical ATG start codon on cryptic antigen expression.
  • To assess the potential of cryptic antigens for cancer immunotherapy.

Main Methods:

  • Generated immortalized mouse progenitor cells (HoxB8) with minigene constructs encoding CTG-driven SIINFEKL (S8L) epitope up- or downstream of an ATG-driven peptide.
  • Treated cells with Toll-like receptor agonists to stimulate innate immunity.
  • Assessed T cell killing of tumor cells expressing cryptic S8L in vitro and tumor progression in vivo.

Main Results:

  • Innate immune stimulation enhanced CTG-S8L translation independently of its position relative to the ATG-initiated ORF.
  • Downstream CTG-S8L translation occurred via leaky scanning or re-initiation.
  • Tumor cells expressing cryptic S8L were efficiently killed by T cells in vitro, and mice with cryptic S8L-expressing tumors showed delayed progression.

Conclusions:

  • Noncanonical start codon-driven cryptic antigen translation is position-independent after innate immune stimulation.
  • Cryptic antigens, even at low expression levels, can be effectively targeted by T cells.
  • Cryptic antigen translation presents a promising avenue for developing novel cancer immunotherapies.

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