Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator

Jing Pan, Qi Zhang, Katie Palen, Li Wang, Lifen Qiao, Bryon Johnson, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background: No effective approaches to target mutant Kras have yet been developed. Immunoprevention using KRAS-specific antigenic peptides to trigger T cells capable of targeting tumor cells relies heavily on lipid metabolism. To facilitate better TCR/peptide/MHC interactions that result in better cancer preventive efficacy, we combined KVax with avasimibe, a specific ACAT1 inhibitor, tested their anti-cancer efficacy in mouse lung cancer models, where Kras mutation was induced before vaccination. Methods: Control of tumor growth utilizing a multi-peptide Kras vaccine was tested in combination with avasimibe in a syngeneic lung cancer mouse model and a genetically engineered mouse model (GEMM). Activation of immune responses after administration of Kras vaccine and avasimibe was also assessed by flow cytometry, ELISpot and IHC. Findings: We found that Kras vaccine combined with avasimibe significantly decreased the presence of regulatory T cells in the tumor microenvironment and facilitated CD8+ T cell infiltration in tumor sites. Avasimibe also enhanced the efficacy of Kras vaccines target mutant Kras. Whereas the Kras vaccine significantly increased antigen-specific intracellular IFN-γ and granzyme B levels in CD8+ T cells, avasimibe significantly increased the number of tumor-infiltrating CD8+ T cells. Additionally, modulation of cholesterol metabolism was found to specifically impact in T cells, and not in cancer cells. Interpretation: Avasimibe complements the efficacy of a multi-peptide Kras vaccine in controlling lung cancer development and growth. This treatment regimen represents a novel immunoprevention approach to prevent lung cancer.

Original languageEnglish (US)
Pages (from-to)72-81
Number of pages10
JournalEBioMedicine
Volume49
DOIs
StatePublished - Nov 2019

Keywords

  • Avasimibe
  • Chemoimmunoprevention
  • Cholesterol metabolism
  • Kras
  • Peptide vaccine
  • T cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator'. Together they form a unique fingerprint.

Cite this