title: Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo.
abstract: Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.
authors.affiliation: Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Shimane, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tongu
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Monma
authors.forename: Touko
authors.initials: T
authors.lastname: Inao
authors.forename: Takaya
authors.initials: T
authors.lastname: Yamada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kawauchi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001119:Arginase / Q000096:biosynthesis; D039481:CD11b Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000032:analysis; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D019707:Receptors, Chemokine / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D039481:CD11b Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D003841:Deoxycytidine; D007371:Interferon-gamma; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase; D000093542:Gemcitabine