Anti-metastatic effects of DNA vaccine encoding single-chain trimer composed of MHC I and vascular endothelial growth factor receptor 2 peptide

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling is the key rate-limiting step in angiogenesis. VEGFR2 serves as the most important target of anti-angiogenic therapy for cancers. Single-chain trimer (SCT) comprising antigen peptide, β2-microglobulin (β2m), and major histocompatibility complex (MHC) class I heavy chain was a particularly powerful strategy involved in the increase of the potency of DNA vaccine against tumors and infections. In the present study, we constructed an SCT-encoding VEGFR2 antigen peptide [aa400-408, also known as kinase insert domain-containing receptor (KDR2)], β2m, and mouse MHC class I heavy chain H-2Db [pcDNA3.1(+)-KDR2-β2m-H-2Db, or SCT-KDR2]. The constructed SCT-KDR2 DNA was efficiently expressed in the human A293 embryonic kidney cell line. Intradermal immunization of C57BL/6 mice with SCT-KDR2 DNA was able to successfully break self-immunological tolerance and induce robust cytotoxic T-lymphocyte (CTL) response to VEGFR2, leading to marked suppression of tumor cell-induced angiogenesis and metastasis in murine models of B16 melanoma and 3LL Lewis lung carcinoma. Taken together, the results showed that VEGFR2-targeted SCT vaccination is an effective modality that can be utilized in anti-angiogenic active immunotherapy for various types of cancer.