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

Luuk Van Hooren,Anna Dimberg,Sara M Mangsbo,Maria Georganaki,Hua Huang

doi:10.18632/oncotarget.10364

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.

Highlights

Tumors evade destruction by the immune system through secretion of immunosuppressive cytokines, recruitment of immunosuppressive cells, altering the antigen-presentation machinery, up-regulation of immune regulatory molecules and induction of endothelial anergy towards effector immune cell recruitment [1]
We have previously shown that a local low-dose of anti-CD40 monoclonal antibody (mAb) is superior to systemic treatment, and that four days of sunitinib treatment is sufficient to induce chemokine expression in B16.F10 tumor endothelial cells [15, 19]
Combining anti-CD40 mAb therapy with sunitinib significantly inhibited tumor growth and increased survival (Figure 1C-1D, Supplementary Figure S1E-S1H). These results show that the combination of sunitinib and anti-CD40 mAb is superior to either monotherapy in B16.F10 melanoma and T241 fibrosarcoma

Summary

Introduction

Tumors evade destruction by the immune system through secretion of immunosuppressive cytokines, recruitment of immunosuppressive cells, altering the antigen-presentation machinery, up-regulation of immune regulatory molecules and induction of endothelial anergy towards effector immune cell recruitment [1]. By targeting molecules involved in regulation of immune cell function in the tumor microenvironment, the immune response toward the tumor can be activated. CD40 is a member of the tumor necrosis factor (TNF) superfamily that has attracted considerable interest in the field of immunotherapy of cancer due to its pivotal role in activation of dendritic cells (DCs) and stimulation of adaptive immunity. CD40 stimulation may result in increased expression of VEGF and thereby promoting tumor angiogenesis [8], and CD40 signaling on myeloid-derived suppressor cells (MDSCs) is required for induction of T-cell tolerance and the accumulation of T regulatory cells (Tregs) in the tumor [9]

Methods

Results

Conclusion