Endothelial dendritic cell vaccines inhibit tumor growth and metastasis of colon cancer through anti-angiogenesis Free

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Background: One novel approach to the treatment of solid cancers involves therapeutic agents that inhibit vascularization of growing tumors. Recent studies have shown that vaccination with the autologous antigens of activated endothelium can inhibit tumor growth and metastasis through induction of anti-angiogenesis. Dendritic cells (DCs) are highly effective antigen-presenting cells and play a pivotal role in T cell-mediated immunity. DCs have been shown to induce strong antitumor immune responses in vitro and in vivo. Moreover, compared with vaccination strategies directed against a single antigen, cell lysate as the source of antigen offers the potential advantage of inducing a broad T-cell response against multiple known, as well as unknown antigens. We hypothesized that an active immunotherapeutic approach targeting endothelial cells might inhibit tumor angiogenesis and metastasis.

Objective: In an attempt to increase the potential clinical applicability of endothelial vaccines, we investigated the ability of dendritic cells pulsed with activated endothelium (EC-DC) to induce specific immunity against tumor angiogenesis, and inhibit tumor growth.

Method: We immunized mice with dendritic cells pulsed with either murine hepatic sinusoidal endothelial cells (HSE-DC) or human umbilical vein endothelial cells (HUVEC-DC) in two syngeneic models of the mouse colon cancer cell line, Colon-26, to examine their effects. Mice were carefully monitored with respect to tumor growth, and the development of side-effects. We also examined whether HUVEC-DC could induce human cytotoxic T lymphocytes (CTLs) specific to the target cells in vitro. Monocyte-derived DCs of healthy donors were pulsed with lysate generated from HUVEC. Specific cytotoxic T lymphocyte (CTL) activity against cultured endothelial cells was tested using in vitro assays.

Result: Vaccination with the respective EC-DC significantly inhibited tumor growth and metastasis, the effect of autologous HSE-DC being more pronounced than that of xenogeneic HUVEC-DC. In addition, the anti-tumor effect of the respective EC-DC was stronger than that of unpulsed DC, and in vitro analysis showed that it could be attributed to the induction of CTLs, specifically recognizing and lyzing activated endothelium but not tumor cells. High levels on IFN-γ could be detected in the supernatants of CTL-HUVEC co-cultures, indicating T-cell immune response.Conclusion: Our present results suggest that endothelial dendritic cell vaccines can overcome peripheral tolerance of self-angiogenic antigens, and support important clinical implications of vaccines targeting tumor angiogenesis.