Translation dysregulation in cancer as a source for targetable antigens

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Aberrant peptides presented by MHC molecules can trigger T cell responses against tumors.
• Cancer cells often exhibit dysregulated protein synthesis, potentially leading to immunogenic aberrant peptides.
• Targeting these aberrant peptides offers a potential strategy for T cell-based cancer therapies.

Purpose of the Study:

• To investigate the role of translational dysregulation in controlling tumors.
• To explore how disrupting translation fidelity impacts tumor immunogenicity and therapeutic response.

Main Methods:

• Deletion of tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells to induce translational errors.
• Analysis of downstream effects on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays.
• In vivo studies assessing tumor growth and response to anti-programmed cell death 1 (PD-1) checkpoint blockade.

Main Results:

• TYW2 knockout (KO) tumor cells produced immunogenic out-of-frame peptides.
• Loss of TYW2 significantly increased tumor immunogenicity.
• TYW2 deficiency sensitized tumors to anti-PD-1 checkpoint blockade therapy in vivo.
• Reduced TYW2 expression in human cancer patients correlated with better response to checkpoint blockade.

Conclusions:

• Defects in translation fidelity, specifically via TYW2 loss, can drive tumor immunogenicity.
• Targeting translational fidelity represents a novel strategy for enhancing cancer immunotherapy.
• Exploiting TYW2-mediated translational errors may improve the efficacy of checkpoint blockade therapies.