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Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and
Yiwen Li1, Mei-Nai Wang, Hongli Li
1ImClone Systems Incorporated, New York, NY 10014, USA. yiwen@imclone.com
Abstract:
The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.
Insights
Active immunotherapy targeting fetal liver kinase 1 (flk1) successfully broke immune tolerance in mice. This approach inhibited tumor angiogenesis and metastasis, offering a potential new strategy for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Vascular Biology
Background:
- Fetal liver kinase 1 (flk1), also known as VEGFR-2 or KDR, is a receptor tyrosine kinase specific to endothelial cells.
- flk1 plays a crucial role in both physiological and pathological angiogenesis, the formation of new blood vessels.
- Tumor angiogenesis is essential for tumor growth and metastasis.
Purpose of the Study:
- To investigate the potential of active immunotherapy targeting flk1 to inhibit tumor angiogenesis and metastasis.
- To determine if immune responses against flk1 can be generated in mice.
Main Methods:
- Immunization of mice with dendritic cells pulsed with a soluble flk1 protein (DC-flk1).
- Assessment of flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses.
- Measurement of tumor-induced angiogenesis using an alginate bead assay.
- Evaluation of pulmonary metastasis development in mice challenged with melanoma and lung carcinoma cells.
- Survival analysis in mice challenged with Lewis lung tumors.
Main Results:
- DC-flk1 immunization successfully elicited flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1.
- Tumor-induced angiogenesis was significantly suppressed in immunized mice.
- Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice.
- DC-flk1 immunization significantly prolonged the survival of mice with Lewis lung tumors.
Conclusions:
- Active immunization targeting flk1 is a viable strategy to inhibit tumor angiogenesis and metastasis.
- This immunotherapy approach holds promise as a potential treatment for angiogenesis-related diseases, including cancer.
- Targeting endothelial-specific antigens like flk1 can effectively disrupt tumor growth and spread.