Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors.
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
Anita E M
AE
Angiogenesis Laboratory, Research Institute for Growth and Development (GROW), Department of Internal Medicine, Maastricht University & University Hospital, Maastricht, The Netherlands.
oude Egbrink
Mirjam G A
MG
Castermans
Karolien
K
van der Schaft
Daisy W J
DW
Thijssen
Victor L J L
VL
Dings
Ruud P M
RP
Kwee
Lucy
L
Mayo
Kevin H
KH
Wagstaff
John
J
Bouma-ter Steege
Jessica C A
JC
Griffioen
Arjan W
AW
D043168:Angiostatins / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017635:Clonal Anergy; D003510:Cyclohexanes; D003520:Cyclophosphamide / Q000494:pharmacology; D015536:Down-Regulation; D043169:Endostatins / Q000494:pharmacology; D042783:Endothelial Cells; D004727:Endothelium / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017239:Paclitaxel / Q000494:pharmacology; D010455:Peptides; D011506:Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000970:Antineoplastic Agents; D003510:Cyclohexanes; D043169:Endostatins; D010455:Peptides; D011506:Proteins; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C111993:betapep-25 protein, synthetic; D018799:Intercellular Adhesion Molecule-1; D043168:Angiostatins; D003520:Cyclophosphamide; D017239:Paclitaxel; D000077609:O-(Chloroacetylcarbamoyl)fumagillol