title: Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment.
abstract: 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Luuk
authors.initials: L
authors.lastname: van Hooren
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Georganaki
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Mangsbo
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy / Q000401:mortality; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D039481:CD11b Antigen; D019013:CD40 Antigens; D007211:Indoles; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000077210:Sunitinib
keywords: CD40; MDSC; T-cell; endothelial activation; sunitinib