Cyclophosphamide Promotes Chronic Inflammation–Dependent Immunosuppression and Prevents Antitumor Response in Melanoma

Alexandra Sevko, Moshe Sade-Feldman, Julia Kanterman, Tillmann Michels, Christine S. Falk, Ludmila Umansky, Marcel Ramacher, Masashi Kato, Dirk Schadendorf, Michal Baniyash, Viktor Umansky
2013 Journal of Investigative Dermatology  
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 þ CD11b þ
more » ... d-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 þ 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.
doi:10.1038/jid.2012.444 pmid:23223128 fatcat:d5nsxjkthvdtzkqpdkw7j5vtoa