Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity. Academic Article uri icon

Overview

abstract

  • Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

authors

publication date

  • July 11, 2022

Research

keywords

  • DNA Polymerase II
  • Neoplasms
  • Poly-ADP-Ribose Binding Proteins

Identity

PubMed Central ID

  • PMC10181095

Scopus Document Identifier

  • 85133836073

Digital Object Identifier (DOI)

  • 10.7303/syn30137113

PubMed ID

  • 35817971

Additional Document Info

volume

  • 54

issue

  • 7