Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma
Low-dose cyclophosphamide (CP) therapy induces immunogenic tumor cell death and decreases regulatory T cell (Treg) numbers in mice with transplantable tumors. Using the ret transgenic murine melanoma model that resembles human melanoma, we detected no beneficial antitumor effects with such treatment...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2013
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| In: |
The journal of investigative dermatology
Year: 2013, Jahrgang: 133, Heft: 6, Pages: 1610-1619 |
| ISSN: | 1523-1747 |
| DOI: | 10.1038/jid.2012.444 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1038/jid.2012.444 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0022202X15362989 
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| Verfasserangaben: | Alexandra Sevko, Moshe Sade-Feldman, Julia Kanterman, Tillmann Michels, Christine S. Falk, Ludmila Umansky, Marcel Ramacher, Masashi Kato, Dirk Schadendorf, Michal Baniyash and Viktor Umansky |
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| 520 | |a Low-dose cyclophosphamide (CP) therapy induces immunogenic tumor cell death and decreases regulatory T cell (Treg) numbers in mice with transplantable tumors. Using the ret transgenic murine melanoma model that resembles human melanoma, we detected no beneficial antitumor effects with such treatment, despite a decrease in Tregs. On the contrary, low-dose CP enhanced the production of chronic inflammatory mediators in melanoma lesions associated with increased accumulation of Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs), which exhibit elevated suppressive activity and nitric oxide (NO) production as well as inhibition of T-cell proliferation. Moreover, the frequencies of CD8+ T cells in the tumors and their ability to produce perforin were decreased. To study whether the observed CP-induced MDSC expansion and activation also occurs under chronic inflammatory tumor-free conditions, mice exhibiting chronic inflammation were treated with CP. Similar to tumor-bearing mice, CP-treated inflamed mice displayed elevated levels of MDSCs with enhanced production of NO, reactive oxygen species, and a suppressed in vivo natural killer (NK) cell cytotoxic activity indicating CP effects on the host immune system independent of the tumor. We suggest that melanoma therapy with low-dose CP could be efficient only when combined with the neutralization of MDSC immunosuppressive function and chronic inflammatory microenvironment. | ||
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