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Anti‐angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte‐endothelium interactions and infiltration in tumors
Author(s) -
Dirkx Anita E. M.,
Egbrink Mirjam G. A. oude,
Castermans Karolien,
Schaft Daisy W. J.,
Thijssen Victor L. J. L.,
Dings Ruud P. M.,
Kwee Lucy,
Mayo Kevin H.,
Wagstaff John,
Steege Jessica C. A. Boumater,
Griffioen Arjan W.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4493com
Subject(s) - angiogenesis , angiostatin , endostatin , in vivo , immunology , cancer research , neovascularization , intravital microscopy , endothelial stem cell , ex vivo , microvessel , immunotherapy , tumor microenvironment , cytotoxic t cell , endothelium , cancer immunotherapy , cell adhesion molecule , biology , immune system , in vitro , biochemistry , microbiology and biotechnology , endocrinology
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 immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, 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 enhanced leukocyte‐vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8 + cytotoxic T lymphocytes, was enhanced markedly. 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 overcome endothelial cell anergy and promote leukocyteendothelium interactions and infiltration in tumors. FASEB J. 20, 621–630 (2006)