title: Improvement of antitumor effect of intratumoral injection of immature dendritic cells into irradiated tumor by cyclophosphamide in mouse colon cancer model.
abstract: Recently, chemotherapy and radiotherapy are known to directly affect some immunosuppressive barriers within a tumor microenviroment. We used cyclophosphamide (CTX), which is known to enhance the immune response by suppressing CD4+CD25+ regulatory T cells (Treg cells) when used at a low dose, as a chemotherapeutic agent to provide a synergic effect in the irradiation and dendritic cells (DC) combination therapy. Some previous studies observed that a single-dose CTX treatment significantly reduced the number of Treg cells in 3-5 days, however, the reduced Treg cells increased rapidly after 5 days. To overcome the disadvantages of a single-dose CTX, we used 30 mg/kg dose of CTX, which was treated intraperitoneally to mice 3 days before every immature DC (iDC) injection (known as "metronomic schedule CTX"). Irradiation was applied at a dose of 10 Gy to the tumor on the right thigh by a linear accelerator. Then, iDC was intratumorally injected into the irradiated tumor site. Growth of a distant tumor on the right and left flank was suppressed by an injection of iDC into the irradiated tumor, and this effect was increased by the metronomic schedule CTX. Also, combinations treated with the metronomic schedule CTX and ionizing radiation (IR)/iDC, showed the longest survival time compared with other groups. This antitumor immune response of IR/iDC was improved by metronomic schedule CTX and this result was associated with decreasing the proportion of CD4+CD25+ Treg cells and increasing the number of tumor-specific interferon-γ-secreting T cells. Our results demonstrated that metronomic schedule CTX improves the antitumor effect of immunization with an injection of DC s into the irradiated tumor.
authors.affiliation: Dongnam Institute of Radiological & Medical Sciences, Busan, Korea.
authors.forename: Cheol-Hun
authors.initials: CH
authors.lastname: Son
authors.forename: Dong Yeok
authors.initials: DY
authors.lastname: Shin
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Kim
authors.forename: Hee-Seong
authors.initials: HS
authors.lastname: Park
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Jung
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Kwangmo
authors.initials: K
authors.lastname: Yang
authors.forename: You-Soo
authors.initials: YS
authors.lastname: Park
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D015704:CD4 Antigens / Q000378:metabolism; D002277:Carcinoma / Q000473:pathology / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000637:transplantation; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000379:methods*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma; D003520:Cyclophosphamide