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Georganaki, Maria
Publications (6 of 6) Show all publications
Roodakker, K. R., Alhuseinalkhudhur, A., Al-Jaff, M., Georganaki, M., Zetterling, M., Berntsson, S. G., . . . Smits, A. (2019). Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity. European Journal of Nuclear Medicine and Molecular Imaging, 46(3), 569-579
Open this publication in new window or tab >>Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-356591 (URN)10.1007/s00259-018-4107-z (DOI)000457151600005 ()30109401 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-04-06Bibliographically approved
Georganaki, M. (2018). Vascular targeting for enhanced cancer immunotherapy. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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)
Opponent
Supervisors
Available from: 2018-02-14 Created: 2018-01-17 Last updated: 2018-03-07
Georganaki, M., van Hooren, L. & Dimberg, A. (2018). Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Frontiers in Immunology, 9, Article ID 3081.
Open this publication in new window or tab >>Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 3081Article, review/survey (Refereed) Published
Abstract [en]

Boosting natural immunity against malignant cells has had a major breakthrough in clinical cancer therapy. This is mainly due to the successful development of immune checkpoint blocking antibodies, which release a break on cytolytic anti-tumor-directed T-lymphocytes. However, immune checkpoint blockade is only effective for a proportion of cancer patients, and a major challenge in the field is to understand and overcome treatment resistance. Immune checkpoint blockade relies on successful trafficking of tumor-targeted T-lymphocytes from the secondary lymphoid organs, through the blood stream and into the tumor tissue. Resistance to therapy is often associated with a low density of T-lymphocytes residing within the tumor tissue prior to treatment. The recruitment of leukocytes to the tumor tissue relies on up-regulation of adhesion molecules and chemokines by the tumor vasculature, which is denoted as endothelial activation. Tumor vessels are often poorly activated due to constitutive pro-angiogenic signaling in the tumor microenvironment, and therefore constitute barriers to efficient leukocyte recruitment. An emerging possibility to enhance the efficiency of cancer immunotherapy is to combine pro-inflammatory drugs with anti-angiogenic therapy, which can enable tumor-targeted T-lymphocytes to access the tumor tissue by relieving endothelial anergy and increasing adhesion molecule expression. This would pave the way for efficient immune checkpoint blockade. Here, we review the current understanding of the biological basis of endothelial anergy within the tumor microenvironment, and discuss the challenges and opportunities of combining vascular targeting with immunotherapeutic drugs as suggested by data from key pre-clinical and clinical studies.

Keywords
angiogenesis, cancer, checkpoint blockade, PD-1, PD-L1, CTLA-4, VEGF, endothelial activation
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-373915 (URN)10.3389/fimmu.2018.03081 (DOI)000454094100002 ()
Funder
Swedish Research Council, Dnr 2016-02495Swedish Cancer Society, CAN 2015/1216Swedish Cancer Society, CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075
Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-01-17Bibliographically approved
Langenkamp, E., Zhang, L., Lugano, R., Huang, H., Elhassan, T. E., Georganaki, M., . . . Dimberg, A. (2015). Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival. Cancer Research, 75(21), 4504-4516
Open this publication in new window or tab >>Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 21, p. 4504-4516Article in journal (Refereed) Published
Abstract [en]

Glioblastoma is an aggressive brain tumor characterized by an abnormal blood vasculature that is hyperpermeable. Here, we report a novel role for CD93 in regulating angiogenesis in this setting by modulating cell-cell and cell-matrix adhesion of endothelial cells. Tissue microarray analysis demonstrated that vascular expression of CD93 was correlated with poor survival in a clinical cohort of patients with high-grade astrocytic glioma. Similarly, intracranial growth in the GL261 mouse model of glioma was delayed significantly in CD93(-/-) hosts, resulting in improved survival compared with wild-type mice. This effect was associated with increased vascular permeability and decreased vascular perfusion of tumors, indicating reduced vessel functionality in the absence of CD93. RNAi-mediated attenuation of CD93 in endothelial cells diminished VEGF-induced tube formation in a three-dimensional collagen gel. CD93 was required for efficient endothelial cell migration and proper cell polarization in vitro. Further, in endothelial cells where CD93 was attenuated, decreased cell spreading led to a severe reduction in cell adhesion, a lack of proper cell contacts, a loss of VE-cadherin, and aberrant actin stress fiber formation. Our results identify CD93 as a key regulator of glioma angiogenesis and vascular function, acting via cytoskeletal rearrangements required for cell-cell and cell-matrix adhesion.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-269008 (URN)10.1158/0008-5472.CAN-14-3636 (DOI)000365602200009 ()26363010 (PubMedID)
Funder
Swedish Cancer Society, CAN 2011/862Swedish Childhood Cancer Foundation, PR2013-0107, PROJ11/083Swedish Research Council, 2013-3797, 2008-2853
Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2017-12-01Bibliographically approved
Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., . . . Dimberg, A. (2015). VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation. The FASEB Journal, 29(1), 227-238
Open this publication in new window or tab >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
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2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 1, p. 227-238Article in journal (Refereed) Published
Abstract [en]

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
Note

Författare två och tre delar andraförfattarskapet.

Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-17Bibliographically approved
Magnusson, K., Fredholm, H., Georganaki, M., Uhlén, M., Fredriksson, I., Dimberg, A. & Pontén, F.Angiogenesis as a risk factor for young women with breast cancer.
Open this publication in new window or tab >>Angiogenesis as a risk factor for young women with breast cancer
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(English)Manuscript (preprint) (Other academic)
Keywords
Angiogenesis, CD93, Prognostic biomarker, Breast cancer, Antibody-based proteomics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264226 (URN)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2016-01-13
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