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

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.

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

“…Administration of avasimibe augments the in vitro cytotoxic effect of these cells, an effect that can be partly explained by an increased ratio of cytotoxic CD8 T cells 114 . This observation is consistent with findings showing that avasimibe treatment effectively promotes CD8 effector T cell function 87,115 . Thus, targeting CE has dual benefits, by repressing cancer cells on the one hand and augmenting CD8 T cell anti-tumour function on the other hand.…”

“…Lung, head and neck cancer, melanoma models 87,115,129 HER2, receptor tyrosine-protein kinase ErbB-2; CRC, colorectal cancer.…”

“…Another strategy is combining cholesterol-esterification inhibitors with immunotherapies, such as anti-cancer vaccines and anti-PD-1 therapy. Although avasimibe treatment effectively inhibits regulatory T cell populations and increases CD8 T cell infiltration in a lung tumour model, a combination of avasimibe with a Kras peptide vaccine has stronger tumour inhibitory effects 115 . Avasimibe can also be combined with a DC vaccine to boost adaptive anti-tumour immunity, as shown in a head and neck cancer model 129 .…”

Recombinant KRAS G12D Protein Vaccines Elicit Significant Anti-Tumor Effects in Mouse CT26 Tumor Models

“…Compared with DTT-FD wt treatment, DTT-FD mut treatment showed a better tumor inhibition effect in our CT26 preventive model (Figures 1C,D), which not only indicates that mutant KRAS G12D epitope is more important than any other non-mutant epitopes but also suggests that the CT26 model is efficient in detecting the Anti-Tumor activity of DTSP or DTT-SP 4 containing the KRAS G12D mutant epitope. Recently, several studies have described the tumor-suppressive effects of their KRAS peptide vaccines in different preventive or therapeutic mouse models (47)(48)(49). However, to the best of our knowledge, we are the first to confirm that both DTSP and DTT-SP 4 show certain Anti-Tumor effects not only in a preventive model but also in a therapeutic model.…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…Hao et al used click chemistry to attach Ava-containing nanoliposomes to the surface of engineered T cells without interfering with their physiological functions [ 26 ]. Finally, studies have shown that TCR transgenic CD8 + T cells and chimeric antigen receptor T cells carrying liposomal AVA have good antitumor effects in mouse models of melanoma and glioblastoma [ 152 ].…”