Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. EBioMedicine 2019 Nov;49:72-81
Date
11/05/2019Pubmed ID
31680003Pubmed Central ID
PMC6945201DOI
10.1016/j.ebiom.2019.10.044Scopus ID
2-s2.0-85074132937 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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.
Author List
Pan J, Zhang Q, Palen K, Wang L, Qiao L, Johnson B, Sei S, Shoemaker RH, Lubet RA, Wang Y, You MMESH terms used to index this publication - Major topics in bold
AcetamidesAcetates
Amino Acid Sequence
Animals
Cancer Vaccines
Cholesterol
Disease Progression
Lung Neoplasms
Mice
Proto-Oncogene Proteins p21(ras)
Sulfonamides
Sulfonic Acids
T-Lymphocytes, Regulatory
Vaccines, Subunit