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Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, 50277-50289 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, no 31, 50277-50289 p.
Keyword [en]
CD40, sunitinib, MDSC, endothelial activation, T-cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-308035DOI: 10.18632/oncotarget.10364ISI: 000385422000111OAI: oai:DiVA.org:uu-308035DiVA: diva2:1049264
Funder
EU, FP7, Seventh Framework Programme, 317445Swedish Childhood Cancer FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Available from: 2016-11-24 Created: 2016-11-23 Last updated: 2016-11-24Bibliographically approved

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van Hooren, LuukGeorganaki, MariaHuang, HuaMangsbo, Sara M.Dimberg, Anna
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