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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.

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.

SUBMITTER: van Hooren L

PROVIDER: S-EPMC5226582 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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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.

van Hooren Luuk L Georganaki Maria M Huang Hua H Mangsbo Sara M SM Dimberg Anna A

Oncotarget 20160701 31

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 ...[more]

PMID: 27385210

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Project description:Simple Summary Despite recent advances in treating metastatic renal cell carcinoma (RCC), many patients develop resistance to therapy, resulting in treatment failure. Sunitinib is one drug used to treat metastasized RCC and resistance eventually develops in most patients. In the present in vitro investigation, sulforaphane, a natural compound known to possess antitumor properties without inducing severe side effects, enhanced the efficacy of sunitinib by preventing tumor growth and proliferation in sunitinib-resistant RCC. Sulforaphane, therefore, could prove beneficial as an integrative component in treating metastasized RCC with sunitinib. Further investigation is required to verify these in vitro findings and to evaluate sulforaphane’s clinical value. Abstract Chronic treatment of renal cell carcinoma (RCC) with the tyrosine kinase inhibitor sunitinib (ST) inevitably induces resistance and tumor re-activation. This study investigated whether adding the natural compound sulforaphane (SFN) with its anti-cancer properties could improve ST efficacy in vitro. The RCC cell lines A498, Caki1, KTCTL26, and 786O were exposed to ST, SFN, or both (dual therapy, DT) before (short-term exposure) and during ST-resistance buildup (long-term 8-week exposure). Tumor growth, proliferation, and clone formation were evaluated, as was cell cycle progression and cell cycle regulating proteins. In nonresistant cells (short-term), DT induced a higher reduction in cell viability in three cell lines as compared to monotherapy with either ST or SFN. Long-term SFN or DT significantly reduced tumor growth and proliferation, whereas ST alone had no effect or even elevated proliferation in three cell lines. SFN or DT (but not ST alone) also blocked clonogenic growth. Both long-term SFN and DT enhanced the number of cells in the S- and/or G2/M-phase. Protein analysis in 786O cells revealed a down-regulation of cyclin dependent kinase (CDK) 1 and 2. CDK2 or Cyclin A knockdown caused reduced 786O growth activity. SFN therefore inhibits or delays resistance to chronic ST treatment.

Dataset Information

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

Publications

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

Similar Datasets

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