title: Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma.
abstract: 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.
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sevko
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.forename: Julia
authors.initials: J
authors.lastname: Kanterman
authors.forename: Tillmann
authors.initials: T
authors.lastname: Michels
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.forename: Marcel
authors.initials: M
authors.lastname: Ramacher
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003520:Cyclophosphamide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse