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

Nat Genet. 2022 Jul;54(7):996-1012. doi: 10.1038/s41588-022-01108-w. Epub 2022 Jul 11.


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.

Publication types

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

MeSH terms

  • Animals
  • DNA Polymerase II / genetics*
  • DNA Polymerase III / genetics
  • Humans
  • Immunotherapy
  • Mice
  • Mutation
  • Neoplasms* / genetics
  • Poly-ADP-Ribose Binding Proteins / genetics*


  • Poly-ADP-Ribose Binding Proteins
  • POLD1 protein, human
  • DNA Polymerase II
  • DNA Polymerase III
  • POLE protein, human