O1.05 * AXITINIB, A SELECTIVE VEGFR-1,-2,-3 TYROSINE KINASE INHIBITOR, INHIBITS TUMOR GROWTH AND INCREASES INFILTRATION OF IMMUNE CELLS IN AN INTRACRANIAL MELANOMA MOUSE MODEL
Authors: S. Du Four, S. K. Maenhout, S. P. Niclou, K. Thielemans, B. Neyns, J. L. Aerts
Journal: Neuro-Oncology (2014)

VEGF is a key mediator of pathological cancer associated neoangiogenesis and immunosuppression. VEGFR targeted therapy holds promise to counteract cancer associated neoangiogenesis but also to alleviate cancer associated immune suppression. Melanoma patients are at high risk for developing brain metastases. These lesions are strongly vascularized and have a high risk for spontaneous bleeding. Melanoma is susceptible to immunotherapy and patients affected by brain metastases might benefit from combining immunotherapy with anti-VEGFR therapy. The aim of this study was to investigate the effect of axitinib, a small molecule tyrosine kinase inhibitor of VEGFRs, on MO4 melanoma cell growth in vitro and on the composition of tumor-infiltrating immune cells in a subcutaneous and intracranial melanoma syngeneic mouse model. We first treated MO4 melanoma cells in vitro with increasing concentrations of axitinib and found no induction of apoptosis. Furthermore, increasing amounts of axitinib had no effect on T-cell proliferation or DC maturation, thus excluding a potential suppressive effect of axitinib on antigen presenting and T-cell function. When subcutaneous tumor-bearing mice were treated with axitinib (oral gavage, 25 mg/kg, bid), tumor growth was strongly inhibited and survival was significantly improved as compared to the control group. Next, subcutaneous and intracranial tumor bearing mice were treated with axitinib. After 7 days of treatment a significant increase in the number of total immune cells (CD45 + cells) within the spleen, subcutaneous and intracranial tumor was observed. Whereas the increase in immune cells within the spleen was most marked for CD3 + CD8 + T cells, a significant increase in the number of CD11b + cells was noted within the tumors. Upon further characterizing of this CD11b+ population, we found that there was a significant increase in cells with a monocytic myeloid derived suppressor cell phenotype (moMDSCs,CD11b + Ly6ChighLy6G-). However, in vitro proliferation assays using highly purified splenic MDSCs showed that moMDSCs isolated from axitinib-treated mice to have a reduced suppressive capacity on CD4+ and CD8+ T cells than those isolated from vehicle-treated mice on a per cell basis. When highly purified tumor MDSCs were used in in vitro proliferation assays we found that moMDSCs isolated from axitinib-treated mice almost lost their suppressive capacity on CD4+ and CD8+ T cells. Based on these observations we conclude that axitinib delays tumor growth, increases survival and is associated with an increased infiltration of the tumor micro-environment with immune cells both in subcutaneous as well as intracranial localizations. Axitinib seems to specifically increase moMDSCs within the CD11b+ cell population but to reduce their suppressive capacity. Further investigation of combination therapies with axitinib and immunotherapy seems warranted.