Antiangiogenic therapy enhances tumor-specific immunity in mice Free

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While angiogenic agents like VEGF and bFGF suppress endothelial adhesion molecule (EAMs, like ICAM and VCAM) expression, thereby reducing leukocyte infiltration into tumors, angiogenesis inhibitors generally act to restore EAM expression on angiogenically-activated endothelial cells (EC), thereby promoting leukocyte infiltration and an immune response in tumors. Here, we show that treatment with angiostatic agents anginex or non-peptide calixarene-based compound 0118 restores EC expression of ICAM, VCAM, and E-selectin at both the protein and mRNA levels in vitro and in vivo. This, in turn, leads to enhanced adhesion of leukocytes to EC. Immunohistochemistry and flow cytometric analysis on tumor tissue/cells (melanoma B16F10, and ovarian MA148) from treated mice, demonstrate an increase in total leukocyte infiltration, particularly in subsets of cytotoxic T-cells (CD8⁺), PMN, and macrophages. On the other hand, regulatory T cells (CD4⁺CD25⁺ Foxp3 ⁺ T cells), which are known to control the induction and effector phase of the immunological defense system, are not preferentially attracted. Furthermore, treatment with anginex or 0118 does not induce proliferation of leukocytes, as the number of circulating leukocytes in peripheral blood remains the same in treated and untreated animals. A high level of expression of CD69 and granzyme B on these cytotoxic T cells, and a blast phenotype suggest that they have seen tumor antigen and are activated through tumor specific receptors. Even though the amount of leukocytes in tumors is increased by treatment, the level of leukocyte activation is not modified by the presence of these angiogenesis inhibitors. These findings suggest that by stimulating anti-tumor immunity through modulation of EAM expression, treatment with anginex or 0118 may improve results from immunotherapy.