title: Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase.
abstract: Cyclophosphamide is a widely used chemotherapeutic drug that was recently applied as either an antiangiogenic/antivasculogenic or an immunostimulatory agent in combination with cancer immunotherapies. It has been previously shown that cyclophosphamide augments the efficacy of antitumor immune responses by depleting CD4+ CD25+ T regulatory cells and increasing both T-lymphocyte proliferation and T memory cells. Furthermore, cyclophosphamide was shown to mediate killing of circulating endothelial progenitors. However, the molecular basis for these observations has not yet been elucidated. We show here that the cyclophosphamide-mediated inhibition of inducible nitric oxide synthase is directly linked to its immunostimulatory but not to its antivasculogenic effects. Moreover, combined application of cyclophosphamide with a novel, oral DNA vaccine targeting platelet-derived growth factor B (PDGF-B), overexpressed by proliferating endothelial cells in the tumor vasculature, not only completely inhibited the growth of different tumor types but also led to tumor rejections in mice. These findings provide a new rationale at the molecular level for the combination of chemotherapy and immunotherapy in cancer treatment.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Jörg A
authors.initials: JA
authors.lastname: Krüger
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D003520:Cyclophosphamide / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005260:Female; D008221:Lymphoid Tissue / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010954:Plasmacytoma / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000276:immunology; D022562:Salmonella Vaccines / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D020574:Proto-Oncogene Proteins c-sis; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated; D019444:Vaccines, DNA; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse