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Vascular targeting for enhanced cancer immunotherapy
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1420
Emneord [en]
cancer immunotherapy, tumor vasculature, endothelial activation, IDO1, ELTD1, tertiary lymphoid organ
HSV kategori
Forskningsprogram
Biologi
Identifikatorer
URN: urn:nbn:se:uu:diva-339114ISBN: 978-91-513-0212-6 (tryckt)OAI: oai:DiVA.org:uu-339114DiVA, id: diva2:1175408
Disputas
2018-03-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds v 20, Uppsala, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-02-14 Laget: 2018-01-17 Sist oppdatert: 2018-03-07
Delarbeid
1. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
Åpne denne publikasjonen i ny fane eller vindu >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
Vise andre…
2015 (engelsk)Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, nr 1, s. 227-238Artikkel i tidsskrift (Fagfellevurdert) 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.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
Merknad

Författare två och tre delar andraförfattarskapet.

Tilgjengelig fra: 2014-12-29 Laget: 2014-12-29 Sist oppdatert: 2018-01-17bibliografisk kontrollert
2. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
Åpne denne publikasjonen i ny fane eller vindu >>Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
Vise andre…
2016 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 31, s. 50277-50289Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
CD40, sunitinib, MDSC, endothelial activation, T-cell
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-308035 (URN)10.18632/oncotarget.10364 (DOI)000385422000111 ()
Forskningsfinansiär
EU, FP7, Seventh Framework Programme, 317445Swedish Childhood Cancer FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Tilgjengelig fra: 2016-11-24 Laget: 2016-11-23 Sist oppdatert: 2018-02-23bibliografisk kontrollert
3. Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
Åpne denne publikasjonen i ny fane eller vindu >>Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-339104 (URN)
Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17
4. Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
Åpne denne publikasjonen i ny fane eller vindu >>Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-339107 (URN)
Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17
5. Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
Åpne denne publikasjonen i ny fane eller vindu >>Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-339110 (URN)
Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17

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