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Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator
- Source :
- EBioMedicine, Vol 49, Iss, Pp 72-81 (2019), EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
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. Keywords: Chemoimmunoprevention, Kras, Peptide vaccine, Avasimibe, Cholesterol metabolism, T cell
- Subjects :
- 0301 basic medicine
Lung Neoplasms
Research paper
lcsh:Medicine
Acetates
medicine.disease_cause
T-Lymphocytes, Regulatory
Mice
0302 clinical medicine
Acetamides
Peptide vaccine
Sulfonamides
lcsh:R5-920
ACAT1
General Medicine
3. Good health
medicine.anatomical_structure
Cholesterol
030220 oncology & carcinogenesis
Vaccines, Subunit
Disease Progression
KRAS
lcsh:Medicine (General)
T cell
Cancer Vaccines
General Biochemistry, Genetics and Molecular Biology
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
medicine
Animals
Cholesterol metabolism
Amino Acid Sequence
neoplasms
Chemoimmunoprevention
Tumor microenvironment
business.industry
lcsh:R
Cancer
Avasimibe
medicine.disease
digestive system diseases
respiratory tract diseases
030104 developmental biology
Cancer cell
Cancer research
Kras
Cancer vaccine
Sulfonic Acids
business
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 49
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....964cef16723d9f33a84d5de67fad245d