VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.
T-cell defects and premature thymic atrophy occur in cancer patients and tumor-bearing animals. We demonstrate that exposure of mice to recombinant vascular endothelial growth factor (VEGF) at concentrations similar to those observed in advanced stage cancer patients reproduces this profound thymic atrophy and is highlighted by a dramatic reduction in CD4+/CD8+ thymocytes. We find that VEGF does not induce thymocyte apoptosis, but instead rapidly decreases the number of the earliest observable progenitors in the thymus. VEGF does not inhibit thymocyte development in fetal thymic organ culture, further suggesting a prethymic effect. We also demonstrate that bone marrow progenitors from animals infused with recombinant VEGF and transferred to irradiated untreated animals recolonize the thymus more efficiently than progenitors from control animals. This suggests that VEGF exposure is associated with an increased population of thymus-committed progenitors in the bone marrow. We hypothesize that pathophysiologically relevant concentrations of VEGF may block the differentiation and/or emigration of these progenitors resulting in the observed thymic atrophy. Removal of VEGF via cessation of infusion or adoptive transfer of progenitors to a congenic host induces a preferential commitment of lymphoid progenitors to the T lineage and results in a restoration of the normal composition and cellularity of the thymus. These data demonstrate that at pathophysiologic concentrations, VEGF interferes with the development of T cells from early hematopoetic progenitor cells and this may contribute to tumor-associated immune deficiencies.
Ohm
Joyce E
JE
Department of Cancer Biology and Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA. joyce.ohm@mcmail.vanderbilt.edu
Gabrilovich
Dmitry I
DI
Sempowski
Gregory D
GD
Kisseleva
Ekaterina
E
Parman
Kelly S
KS
Nadaf
Sorena
S
Carbone
David P
DP
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D001854:Bone Marrow Cells; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes; D002453:Cell Cycle; D002454:Cell Differentiation; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D009924:Organ Culture Techniques; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000196:embryology / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A