Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment.
CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb led to increased activation of CD11c+ dendritic cells in the tumor draining lymph node, while sunitinib treatment reduced vessel density and decreased accumulation of CD11b+Gr1+ myeloid derived suppressor cells. The expression of ICAM-1 and VCAM-1 adhesion molecules was up-regulated on tumor endothelial cells only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced intratumoral infiltration of CD8+ cytotoxic T-cells. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exerts potent complementary antitumor effects mediated by dendritic cell activation, a reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T-cells.
['van Hooren|Luuk|L|', 'Georganaki|Maria|M|', 'Huang|Hua|H|', 'Mangsbo|Sara M|SM|', 'Dimberg|Anna|A|']
D000818:Animals D000911:Antibodies, Monoclonal D000970:Antineoplastic Agents D039481:CD11b Antigen D019013:CD40 Antigens D045744:Cell Line, Tumor D003713:Dendritic Cells D004357:Drug Synergism D042783:Endothelial Cells D005354:Fibrosarcoma D007211:Indoles D018799:Intercellular Adhesion Molecule-1 D053208:Kaplan-Meier Estimate D008297:Male D008546:Melanoma, Experimental D051379:Mice D008810:Mice, Inbred C57BL D000072737:Myeloid-Derived Suppressor Cells D011758:Pyrroles D000077210:Sunitinib D013602:T-Lymphocytes, Cytotoxic D015854:Up-Regulation D019010:Vascular Cell Adhesion Molecule-1
sunitinib MDSC endothelial activation T-cell CD40