Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

Area of Science:

• Genomic instability
• Cancer immunology
• Immunotherapy

Background:

• Genomic fidelity pathway defects are linked to enhanced immune checkpoint blockade (ICB) therapy response.
• Pathogenic mutations in POLE/POLD1 can cause hypermutation, but their precise impact on antitumor immunity and ICB efficacy remains incompletely understood.

Purpose of the Study:

• To comprehensively evaluate the effect of POLE/POLD1 mutations on ICB efficacy.
• To elucidate the mechanistic basis by which these mutations influence tumor immunity.

Main Methods:

• Utilized murine syngeneic tumor models with Pole/Pold1 functional mutations.
• Analyzed patient tumor data to identify POLE/POLD1 mutation-associated mutational signatures.
• Developed a signature-based model to predict ICB response.
• Investigated the biochemical properties of neoantigens generated by these mutations.

Main Results:

• Pole/Pold1 mutated murine tumors showed enhanced antitumor immunity and ICB sensitivity.
• Patients with POLE/POLD1 mutated tumors and specific mutational signatures responded better to ICB.
• A novel signature-based model accurately identified patients benefiting from ICB, outperforming traditional methods.
• Mutational signatures correlated with neoantigen biochemical features, including increased hydrophobicity in T cell receptor-contact residues.

Conclusions:

• Functional POLE/POLD1 mutations enhance antitumor immunity and ICB efficacy.
• Mutational signatures associated with POLE/POLD1 dysfunction serve as predictive biomarkers for ICB response.
• Altered neoantigen properties, particularly increased hydrophobicity, may facilitate T cell recognition and improve immunotherapy outcomes.