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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, p. 50277-50289Article 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, p. 50277-50289
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, id: 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: 2018-02-23Bibliographically approved
In thesis
1. Vascular targeting for enhanced cancer immunotherapy
Open this publication in new window or tab >>Vascular targeting for enhanced cancer immunotherapy
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.

The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.

In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.

In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.

Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1420
Keyword
cancer immunotherapy, tumor vasculature, endothelial activation, IDO1, ELTD1, tertiary lymphoid organ
National Category
Cell and Molecular Biology Immunology Cancer and Oncology
Research subject
Biology
Identifiers
urn:nbn:se:uu:diva-339114 (URN)978-91-513-0212-6 (ISBN)
Public defence
2018-03-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds v 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-02-14 Created: 2018-01-17 Last updated: 2018-03-07
2. Antibody-based immunotherapy of cancer: From optimization to novel approaches
Open this publication in new window or tab >>Antibody-based immunotherapy of cancer: From optimization to novel approaches
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibody immunotherapy is a successful therapeutic approach to treat cancer. The overall aim of this thesis is to investigate the mechanisms of antibody-based immunotherapies and the role of the tumor microenvironment in mediating the anti-tumor immune response, in order to aid the development of improved immunotherapies for cancer patients.

Agonistic CD40 antibodies activate dendritic cells and improve anti-tumor T-cell responses. In Paper I we demonstrate that their efficacy can be enhanced by co-treatment with sunitinib, a multi-targeted tyrosine kinase inhibitor. The combination therapy restrains immunosuppression, synergistically increases endothelial activation and improves tumor T-cell recruitment, resulting in restrained tumor growth and prolonged survival.  

CTLA-4 and PD-1 negatively regulate the anti-tumor T-cell response and blocking these immune checkpoints with antibodies enhances anti-tumor immunity. However, CTLA-4 checkpoint blockade is associated with severe adverse events. In Paper II, a local low-dose administration of CTLA-4 antibodies is demonstrated to be equally effective as systemic administration in treating experimental bladder cancer. Importantly, antibody spread is reduced, indicating that local administration may be an effective strategy to reduce side effects associated with CTLA-4 blockade.

Tumor-derived expression of Galectin-1 enhances angiogenesis and suppresses anti-tumor immunity. In Paper III, endogenous antibodies are induced against Gal-1 using TRX-Gal-1 fusion proteins to break self-tolerance. Vaccination induces anti-Gal-1 endogenous antibodies, resulting in improved vessel perfusion, improved immune-cell infiltration and decreased tumor growth.

Immunotherapy for glioma is constrained by the immunosuppressive microenvironment. In Paper IV we demonstrate that in vivo activation of B cells enhances tertiary lymphoid structure formation in the brain. Mice with induced tertiary lymphoid structures have an increase of B cells with a regulatory phenotype and CD8+ T-cell activation is suppressed. The response to PD-1 checkpoint blockade is also inhibited, suggesting tertiary lymphoid structures impair the response to immunotherapy.

This thesis demonstrates that immunotherapy can be improved by the addition of anti-angiogenic drugs and that local administration of antibodies is a feasible alternative to the systemic administration conventionally used in the clinic. In addition, therapeutic vaccination and induction of tertiary lymphoid structures by agonistic CD40 antibodies are novel approaches to employ antibodies to modulate the anti-tumor immune response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1433
Keyword
Cancer immunotherapy, CD40, CTLA-4, PD-1, Gal-1, tertiary lymphoid structures
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-342799 (URN)978-91-513-0246-1 (ISBN)
Public defence
2018-04-13, Rudbecksalen, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-03-23 Created: 2018-02-23 Last updated: 2018-04-24

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