Transient activation of tumoral DNA damage tolerance pathway coupled with immune checkpoint blockade exerts durable tumor regression in mouse melanoma

Ming Zhuo, Falih M. Gorgun, Douglas S. Tyler, Ella W. Englander

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Major advances in cancer therapy rely on engagement of the patient’s immune system and suppression of mechanisms that impede the antitumor immune response. Among the most notable is immune checkpoint blockade (ICB) therapy that releases immune cells from suppression. Although ICB has had significant success particularly in melanoma, it eradicates tumors in subsets of patients and sequencing data across different cancers suggest that tumors with high mutational loads are more likely to respond to ICB. This is consistent with the premise that greater tumoral mutational loads contribute to formation of neoantigens that spur the body’s antitumor immune response. Prompted by strong evidence supporting the therapeutic benefits of neoantigens in the context of ICB, we have developed a mouse melanoma combination treatment, where intratumoral administration of DNA-damaging drug transiently activates intrinsic mutagenic DNA damage tolerance pathway and improves success rates of ICB. Using the YUMM1.7 cells melanoma model, we demonstrate that intratumoral delivery of cisplatin activates translesion synthesis DNA polymerases-catalyzed DNA synthesis on damaged DNA, which when coupled with ICB regimen, elicits durable tumor regression. We expect that this new combination protocol affords insights with clinical relevance that will help expand the range of patients who benefit from ICB therapy.

Original languageEnglish (US)
Pages (from-to)605-617
Number of pages13
JournalPigment Cell and Melanoma Research
Volume34
Issue number3
DOIs
StatePublished - May 2021

Keywords

  • DNA damage
  • TLS DNA polymerases
  • cisplatin
  • immune checkpoint blockade
  • melanoma
  • tumor mutation load
  • tumor regression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Oncology
  • Dermatology

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