Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2.
The breaking of immune tolerance of "self-antigens" associated with angiogenesis is an attractive approach to cancer therapy by active immunity. We used vascular endothelial growth factor receptor-2 (VEGFR-2) as a model antigen to explore the feasibility of the immunotherapy with a vaccine based on a xenogeneic homologous protein. To test this concept, we prepared a quail homologous VEGFR-2 protein vaccine (qVEGFR) based on quail VEGFR-2. At the same time, a protein vaccine based on the corresponding ligand-binding domain of mouse self-VEGFR-2 (mVEGFR) was also prepared and used as a control. We found that immunotherapy with qVEGFR was effective at protective and therapeutic antitumor immunity in several solid and hematopoietic tumor models in mice. Autoantibodies against mouse VEGFR-2 (Flk-1) were identified by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Anti-VEGFR antibody-producing B cells were detectable by ELISPOT. Endothelial deposition of immunoglobulins developed within tumor. VEGF-mediated endothelial cell proliferation was inhibited in vitro by immunoglobulins from qVEGFR-immunized mice. Antitumor activity was caused by the adoptive transfer of the purified immunoglobulins. Antitumor activity and production of autoantibodies against Flk-1 could be abrogated by the depletion of CD4+ T lymphocytes. Angiogenesis was apparently inhibited within the tumors, and the vascularization of alginate beads was also reduced. No marked toxicity was found in the immunized mice. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factor receptor associated with angiogenesis in a cross-reaction with single xenogeneic homologous protein.
Key Laboratory of Biotherapy of Human Diseases and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, No. 37, Chengdu, Sichuan, 610041, The People's Republic of China.
Ji-Yan
JY
Liu
Yu-Quan
YQ
Wei
Li
L
Yang
Xia
X
Zhao
Ling
L
Tian
Jian-Mei
JM
Hou
Ting
T
Niu
Fen
F
Liu
Yu
Y
Jiang
Bing
B
Hu
Yang
Y
Wu
Jing-Mei
JM
Su
Yan-Yan
YY
Lou
Qiu-Ming
QM
He
Yan-Jun
YJ
Wen
Jin-Liang
JL
Yang
Bing
B
Kan
Yong-Qiu
YQ
Mao
Feng
F
Luo
Feng
F
Peng
D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D019496:Cancer Vaccines / Q000494:pharmacology* / Q000633:toxicity; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000628:therapy; D010954:Plasmacytoma / Q000276:immunology / Q000628:therapy; D011784:Quail; D016176:T-Lymphocyte Subsets / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
D015478:Antigens, Heterophile; D001323:Autoantibodies; D019496:Cancer Vaccines; D040301:Vascular Endothelial Growth Factor Receptor-2