CD8 T-Cell Induction against Vascular Endothelial Growth Factor Receptor 2 by Salmonella for Vaccination Purposes against a Murine Melanoma

Abstract

The Salmonella type III secretion system (T3SS) efficiently translocates heterologous proteins into the cytosol of eukaryotic cells. This leads to an antigen-specific CD8 T-cell induction in mice orally immunized with recombinant Salmonella. Recently, we have used Salmonella's T3SS as a prophylactic and therapeutic intervention against a murine fibrosarcoma. In this study, we constructed a recombinant Salmonella strain translocating the immunogenic H-2Db-specific CD8 T-cell epitope VILTNPISM (KDR2) from the murine vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a member of the tyrosine protein kinase family and is upregulated on proliferating endothelial cells of the tumor vasculature. After single orogastric vaccination, we detected significant numbers of KDR2-tetramer-positive CD8 T cells in the spleens of immunized mice. The efficacy of these cytotoxic T cells was evaluated in a prophylactic setting to protect mice from challenges with B16F10 melanoma cells in a flank tumor model, and to reduce dissemination of spontaneous pulmonary melanoma metastases. Vaccinated mice revealed a reduction of angiogenesis by 62% in the solid tumor and consequently a significant decrease of tumor growth as compared to non-immunized mice. Moreover, in the lung metastasis model, immunization with recombinant Salmonella resulted in a reduction of the metastatic melanoma burden by approximately 60%.

A Novel Approach on Thalidomide and their Analogues with their Therapeutic uses and Clinical Application

“…DNA immunizations focusing on VEGFR2 of the tumor vasculature have been appeared to repress tumor angiogenesis and both modern and built up metastatic stores [55]. Jellbauer may initiate CD81 cells by immunising creatures with a recombinant Salmonella strain carrying a CD8 epitope from VEGFR2 [56]. Within the B16-F10 melanoma tumor show, the vaccinated creatures appeared acceptance of VEGFR2-specific CD81 populace, which would have focused on the VEGFR2 communicating tumor vascular endothelium and diminished metastatic spread into the lungs and decreased tumor development.…”

Vaccination approach to anti-angiogenic treatment of cancer

“…A vaccine based on an attenuated Salmonella strain expressing a fusion gene product consisting of the immunodominant epitope of the murine VEGFR2 fused to the defined N-terminal translocation domain of the type III effector molecule Yersinia outer protein E (YopE) was developed by Jellbauer et al [55]. In a prophylactic immunization model mice were oro-gastrically immunized once and 30 days later they were challenged with tumor cells.…”

Salmonella and cancer: from pathogens to therapeutics.

“…Instead of sequences encoding TAAs alone, the constructs coding for chimeric proteins consisting of a tumor antigen preceded by an N-terminal fragment of a bacterial protein subjected to T3SS export (containing secretion and translocation signals) were placed in the Salmonella plasmid. These included peptides derived from the SopE, SseF and YopE proteins (Jellbauer et al, 2012;Manuel et al, 2011;Nishikawa et al, 2006;Zhu et al, 2010). The chimeric transgenes were usually placed under bacterial promoters activated after invasion of the host cell.…”

“…Not only survivin but also other proteins overproduced in endothelium during angiogenesis, such as VEGFR2, one of the VEGF receptors, or endoglin, a component of the TGFβ (Transforming Growth Factor beta) receptor complex, have been chosen as targets for Salmonella-based vaccines (Jarosz et al, 2013;Jellbauer et al, 2012). The induction of the CTL response against these antigens should reduce angiogenesis and destroy tumor vasculature leading to inhibition of tumor development.…”

“…The induction of the CTL response against these antigens should reduce angiogenesis and destroy tumor vasculature leading to inhibition of tumor development. Indeed, Salmonella carrying a plasmid encoding a fusion protein comprising the YopE secretion sequence and the fragment of VEGFR2 containing the CD8 + Tcell epitope efficiently limited the growth of B16F10 melanoma in both prophylactic and therapeutic settings (Jellbauer et al, 2012). The authors hypothesized that the vaccine may also affect the immunosuppresive tumor microenvironment by destroying the VEGFR2-positive subset of Treg lymphocytes.…”