Research Papers:

Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment

Luuk van Hooren, Maria Georganaki, Hua Huang, Sara M. Mangsbo and Anna Dimberg _

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Oncotarget. 2016; 7:50277-50289. https://doi.org/10.18632/oncotarget.10364

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Luuk van Hooren1,*, Maria Georganaki1,*, Hua Huang1, Sara M. Mangsbo1,#, Anna Dimberg1,#

1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

*These first authors contributed equally to the work

#These authors have contributed equally to the work

Correspondence to:

Anna Dimberg, email: [email protected]

Keywords: CD40, sunitinib, MDSC, endothelial activation, T-cell

Received: November 11, 2015    Accepted: June 12, 2016    Published: July 1, 2016


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.

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