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.
Liu
Ji-Yan
JY
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.
Wei
Yu-Quan
YQ
Yang
Li
L
Zhao
Xia
X
Tian
Ling
L
Hou
Jian-Mei
JM
Niu
Ting
T
Liu
Fen
F
Jiang
Yu
Y
Hu
Bing
B
Wu
Yang
Y
Su
Jing-Mei
JM
Lou
Yan-Yan
YY
He
Qiu-Ming
QM
Wen
Yan-Jun
YJ
Yang
Jin-Liang
JL
Kan
Bing
B
Mao
Yong-Qiu
YQ
Luo
Feng
F
Peng
Feng
F
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