Anti‐angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte‐endothelium interactions and infiltration in tumors

Abstract

Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immu- nohistochemistry in two mouse tumor models. Angio- genesis inhibitors anginex, endostatin, and angiosta- tin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the en- hanced leukocyte-vessel interactions led to an in- crease in the numbers of tumor infiltrating leuko- cytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infil- trated leukocytes (CD45), as well as the number of CD8 cytotoxic T lymphocytes, was enhanced mark- edly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis.—Dirkx, A. E. M., oude Egbrink, M. G. A., Castermans, K., van der Schaft, D. W. J., Thijssen, V. L. J. L., Dings, R. P. M., Kwee, L., Mayo, K. H., Wagstaff, J., Bouma-ter Steege, J. C. A., Griffioen, A. W. Anti-angiogenesis therapy can over- come endothelial cell anergy and promote leukocyte- endothelium interactions and infiltration in tumors. FASEB J. 20, 621-630 (2006)