DNA-based vaccines activate innate and adaptive antitumor immunity by engaging the NKG2D receptor

Abstract

The interaction of NKG2D, a stimulatory receptor expressed on natural killer (NK) cells and activated CD8 ؉ T cells, and its ligands mediates stimulatory and costimulatory signals to these cells. Here, we demonstrate that DNA-based vaccines, encoding syngeneic or allogeneic NKG2D ligands together with tumor antigens such as survivin or carcinoembryonic antigen, markedly activate both innate and adaptive antitumor immunity. Such vaccines result in highly effective, NK؊ and CD8 ؉ T cell-mediated protection against either breast or colon carcinoma cells in prophylactic and therapeutic settings. Notably, this protection was irrespective of the NKG2D ligand expression level of the tumor cells. Hence, this strategy has the potential to lead to widely applicable and possibly clinically useful DNA-based cancer vaccines.NK cells ͉ NKG2D ligands ͉ T cells ͉ survivin ͉ Peyer's patches

RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

“…Accordingly, Andreas Diefenbach et al (23) demonstrated the efficacy of using NKG2D ligands as components of vaccine, which may offer new approaches for malignancies. Moreover, it was shown that DNA-based vaccines encoding syngeneic or allogeneic NKG2D ligands together with tumor antigens could markedly activate both innate and adaptive anti-tumor immunity (24,25 …”

Hyperthermia increases the therapeutic efficacy of survivinT34A in mouse tumor models

“…6,29,40,41 They were cultured in RPMI-1640 medium supplemented with 10% FBS and 100 μg/ ml amikacin at 37°C with 5% CO 2 atmosphere. The culture medium was replaced with fresh medium every 2-3 d.…”

“…3 By contrast, survivin is prominently overexpressed in most malignant tumors, especially in colon cancer, such as SW480, HCT116 and CT26 and so on. [4][5][6][7] Furthermore, overexpression of survivin frequently correlated with resistance against cancer therapy-induced apoptosis, unfavorable prognosis and abbreviated overall survival. 8 Obviously, the distribution and expression of survivin in vivo has made it a promising target for cancer therapy, 1,9 since downregulation of survivin expression in tumors induces apoptosis and inhibits tumor growth with little toxicity to normal tissues.…”

Expression of the NKG2D ligand UL16 binding protein‐1 (ULBP‐1) on dendritic cells

“…NKG2D ligand expression and peptide presentation was targeted to antigen-presenting cells by DNA-based vaccination, as mice received plasmids containing the sequences for NKG2D ligand, H60 and tumor antigen peptides orally. In two distinct colon carcinoma models, this type of vaccination effectively inhibited tumor growth [25]. The vaccination elicited an effective specific T cell response and enhanced NK cell activity.…”

“…In the same line, this work demonstrated that tumor lines expressing NKG2D ligand evoke a strong CD8 + memory response towards the specific cell lines. Notably, the group of Reisfeld recently demonstrated the potential of NKG2D ligands to enhance specific T cell responses [25]. NKG2D ligand expression and peptide presentation was targeted to antigen-presenting cells by DNA-based vaccination, as mice received plasmids containing the sequences for NKG2D ligand, H60 and tumor antigen peptides orally.…”