title: Gemcitabine treatment enhanced the anti-tumor effect of cytokine induced killer cells by depletion of CD4+CD25briregulatory T cells.
abstract: Cytokine induced killer (CIK) cells have a powerful tumor cells killing activity both in vitro and in vivo and transfusion of these cells have become an adjuvant treatment for tumors. CIK cells are induced and amplified from peripheral blood mononuclear cells (PBMCs) with multiple cytokines. As CD4+CD25briregulatory T cells can be also induced by high dose of interleukin 2 (IL-2) which is used for CIK cells amplification in the CIK cell culture system, the anti-tumor activity of CIK cells was suppressed to some extent. In order to overcome this unwanted suppressive factor, we found that low dose of gemcitabine could reduce the proportion of CD4+CD25briregulatory T cells in the CIK cell culture system and significantly enhance the anti-tumor activity of CIK cells in vitro. The levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) were also reduced significantly following the depletion of CD4+CD25briregulatory T cells in gemcitabine treated CIK cell culture system. In vivo experiment showed that low dose of gemcitabine treated CIK cells significantly suppressed tumor growth and prolonged their lifespan in tumor-bearing nude mice, with the proportion of CD4+CD25briregulatory T cells reduced. Meanwhile, we detected lower levels of IL-10, TGF-β and a higher level of interferon-γ (IFN-γ) in tumor-bearing nude mice that received gemcitabine treated CIK cells transfusion than those in other groups. The possible mechanism involved in the enhanced anti-tumor activity in vivo was that gemcitabine treated CIK cells created a strengthened anti-tumor immune microenvironment with the changed levels of cytokines such as IL-10, TGF-β and IFN-γ. These results suggested a strategy to improve the adoptive immune therapy in recent use by removing the suppressive factors and a more effective tumor treatment combining chemotherapy and immunotherapy.
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Danni
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Transfusion Medicine, Qingdao Blood Center, Qingdao 266071, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Daiqing
authors.initials: D
authors.lastname: Gao
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wei
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Xihe
authors.initials: X
authors.lastname: Xie
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Li
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, PR China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao 266042, PR China. Electronic address: qingming_677@163.com.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055612:Cytokine-Induced Killer Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D016207:Cytokines; D007166:Immunosuppressive Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Gemcitabine cytokine induced killer cells CD4(+)CD25(bri) regulatory T cells cytotoxicity