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Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-339110OAI: oai:DiVA.org:uu-339110DiVA, id: diva2:1174730
Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-01-17
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
Keywords
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)
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Supervisors
Available from: 2018-02-14 Created: 2018-01-17 Last updated: 2018-03-07

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