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Verfasst von:Umansky, Viktor [VerfasserIn]   i
 Sevko, Alexandra [VerfasserIn]   i
Titel:Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation
Verf.angabe:Viktor Umansky, Alexandra Sevko
Jahr:2012
Umfang:8 S.
Fussnoten:Gesehen am 04.10.2018 ; Article was published online on 27 November 2011
Titel Quelle:Enthalten in: Cancer immunology immunotherapy
Ort Quelle:Berlin : Springer, 1976
Jahr Quelle:2012
Band/Heft Quelle:61(2012), 2, Seite 275-282
ISSN Quelle:1432-0851
Abstract:Malignant melanoma is known by its rapid progression and poor response to currently applied treatments. Despite the well-documented melanoma immunogenicity, the results of immunotherapeutic clinical trials are not satisfactory. This poor antitumor reactivity is due to the development of chronic inflammation in the tumor microenvironment characterized by infiltrating leukocytes and soluble mediators, which lead to an immunosuppression associated with cancer progression. Using the ret transgenic mouse melanoma model that closely resembles human melanoma, we demonstrated increased levels of chronic inflammatory factors in skin tumors and metastatic lymph nodes, which correlated with tumor progression. Furthermore, Gr1+CD11b+ myeloid-derived suppressor cells (MDSC), known to block tumor-reactive T cells, were enriched in melanoma lesions and showed an enhanced immunosuppressive capacity. This MDSC accumulation was associated with a strong TCR ζ-chain downregulation in T cells suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon administration of phosphodiesterase-5 inhibitor sildenafil or paclitaxel in non-cytotoxic doses, we observed reduced levels of chronic inflammatory mediators in association with decreased MDSC amounts and immunosuppressive function. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of beneficial outcome of both drugs, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.
DOI:doi:10.1007/s00262-011-1164-6
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: http://dx.doi.org/10.1007/s00262-011-1164-6
 Volltext: https://doi.org/10.1007/s00262-011-1164-6
 DOI: https://doi.org/10.1007/s00262-011-1164-6
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Chronic inflammation
 CITIM 2011
 Immunosuppression
 Melanoma
 Myeloid-derived suppressor cells
 Tumor microenvironment
K10plus-PPN:1581536666
Verknüpfungen:→ Zeitschrift

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