Combined Osteopontin Blockade and Type 2 Classical Dendritic Cell Vaccination as Effective Synergetic Therapy for Conjunctival Melanoma.

Autor:	Peil J; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Vossen C; MPI for Metabolism Research, Cologne, Germany., Bock F; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Center for Molecular Medicine, University of Cologne, Cologne, Germany., Clahsen T; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Center for Molecular Medicine, University of Cologne, Cologne, Germany., Schiller P; Faculty of Medicine and University Hospital Cologne, Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany., Heindl LM; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Bosch JJ; Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands., Wunderlich FT; MPI for Metabolism Research, Cologne, Germany.; Center for Molecular Medicine, University of Cologne, Cologne, Germany., Cursiefen C; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Center for Molecular Medicine, University of Cologne, Cologne, Germany., Schlereth SL; Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2024 Feb 01; Vol. 212 (3), pp. 487-499.
DOI:	10.4049/jimmunol.2300063
Abstrakt:	Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103- type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103- cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor-derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects. (Copyright © 2024 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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