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Area of Science:

  • Genetics
  • Immunology
  • Cancer Biology

Background:

  • Mutations in DNA polymerases POLD1 and POLE are linked to increased cancer incidence, elevated tumor mutation burden (TMB), and improved response to immune checkpoint blockade (ICB).
  • Understanding how TMB influences tumor biology and immunotherapy response is crucial, as not all TMB-high tumors respond to ICB.

Purpose of the Study:

  • To investigate the impact of POLD1 and POLE mutations on cancer development, TMB, and response to ICB in a mouse model.
  • To explore the potential of ICB as a cancer prevention strategy in individuals at high risk.

Main Methods:

  • Generated mice with germline and conditional mutations in the exonuclease domains of Pold1 and Pole.
  • Analyzed spontaneous cancers for TMB and mutational signatures.
  • Assessed tumor response to ICB in established tumors and in a preventative setting.

Main Results:

  • Engineered mice developed spontaneous cancers (lymphomas, lung, intestinal, skin) with increased TMB and human-relevant mutational signatures.
  • Pold1 mutant tail tumors showed high TMB but only partial ICB response; ICB did not improve survival in Kras/Trp53-driven lung cancer models.
  • Early ICB treatment in mutator mice delayed cancer onset and improved survival, selecting for tumors without aneuploidy.

Conclusions:

  • POLD1 and POLE mutations drive cancer with high TMB, but established tumors may not fully respond to ICB due to factors like immune editing.
  • Early administration of ICB shows promise as a cancer prevention strategy for high-risk individuals, delaying cancer onset and improving survival.