Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors.
Langerhans cells (LC), the APCs in the skin, serve as a model for investigation of dendritic cell (DC) function in tissues. DC play a crucial role in the generation of antitumor immune responses. In this study, we investigated the effect of the presence of tumor in vivo on the ability of LC to take up Ag, migrate to draining lymph nodes, and stimulate primary T cell responses. In two animal models, these functions were substantially inhibited. This effect was not restricted to LC located in the skin near a tumor but was also seen at sites distant from the tumor. The duration of tumor exposure, and not its ultimate size, were found to be important, suggesting that tumors could be inhibiting the maturation of LC rather than directly inhibiting their function. Model experiments with radiation chimeras supported this hypothesis. To investigate the potential role of vascular endothelial growth factor (VEGF) in these effects we used anti-VEGF-neutralizing Ab to treat animals bearing tumors. Treatment with the Ab at a dose of 10 microg i.p. per mouse, twice a week for 4 wk, significantly improved the number and function of LC as measured by their ability to migrate to lymph nodes and stimulate primary T cell responses, even at doses that do not affect the growth of these established poorly immunogenic tumors. Thus, inhibition of VEGF signaling may improve DC function in tumor-bearing hosts and possibly serve to improve the efficacy of cancer immunotherapy.
Ishida
T
T
Department of Medicine and Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6838, USA.
Oyama
T
T
Carbone
D P
DP
Gabrilovich
D I
DI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D002465:Cell Movement; D002630:Chemotactic Factors / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006410:Hematopoiesis; D007116:Immunization, Passive; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D007801:Langerhans Cells / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011828:Radiation Chimera; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002630:Chemotactic Factors; D016228:Endothelial Growth Factors; D005456:Fluorescent Dyes; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016650:Fluorescein-5-isothiocyanate