Mechanism of IL‐12's suppression of VEGFR3 upregulation on tumor vessels

IL‐12 is a powerful anticancer agent in many tumor models, but how IL‐12 exerts its anti‐tumoral effect in vivo is still largely unknown. We are exploring this using B16, a C57BL/6‐derived melanoma line transfected to express IL‐12 (B16/IL‐12), a system that provides constant, IL‐12 production within the tumor microenvironment. We have shown that the presence of intratumoral IL‐12 delays tumor growth, and causes phenotypic changes in the blood vasculature. The vessels within B16/IL‐12 tumors have a more normal morphology and fail to upregulate expression of the angiogenic vessel marker, vascular endothelial growth factor receptor 3 (VEGFR3). Studies performed in transgenic mice have shown that the failure to upregulate VEGFR3 is mediated by IFN‐γ and that T cells are required for this effect. We hypothesize that IFN‐γ is acting directly on the endothelial cells to prevent upregulation of VEGFR3. This is being tested with IFN‐γ receptor knock out mice in a bone marrow chimera system. IL‐12 also stimulates the immune system resulting in a marked increase in the number of tumor infiltrating lymphocytes (TILs) and more of these are producing IFN‐γ. These studies suggest that the vascular effects of immunotherapy may be as important to the beneficial effects of immunotherapy on tumor growth as the effects on the immune cells themselves. Supported by NIH R01‐CA28332