title: Low-dose splenic radiation inhibits liver tumor development of rats through functional changes in CD4+CD25+Treg cells.
abstract: The increased number of CD4(+)CD25(+)Treg cells in tumor local and peripheral splenic tissues is related to the low immune function as well as to tumor recurrence and metastasis. Our pre-clinical studies showed that low-dose radiation (LDR) of the spleen in liver cancer patients significantly improves immune functions. However, the molecular mechanisms of such radiation remained ill defined. This study explores the role of CD4(+)CD25(+)Treg cells in radiation-induced immunomodulatory effects. Using the diethylnitrosamine (DEN)-induced rat liver tumor model and in vitro cell experiments, the percentage of CD4(+)CD25(+)Treg/CD4(+) cells in the blood and the expressions of Foxp3(+), IL-10, TGF-β, and cytotoxic T lymphocyte-associated antigen-4(CTLA-4) in spleen and liver tumors significantly decreased after LDR of the spleen in rats with liver cancer. The tumors became smaller than those in the non-radiated group, with both showing a parallel relation. Flow cytometry and MTT results revealed that LDR failed to inhibit CD4(+)CD25(+)Treg cell proliferation. Conversely, apoptosis was reduced and proliferation was stimulated. This process also changed CTLA-4 molecule expression on the surfaces of CD4(+)CD25(+)Treg cells and reduced their inhibitory function against CD4(+)CD25(-)T cell proliferation, and the suppression function of CD4(+)CD25(+)Treg cells was further weakened with the introduction of the CTLA-4 inhibitor. Findings demonstrate that the reduction of CTLA-4 expression on the CD4(+)CD25(+)Treg cell surface and the further inhibition of cell function may be considered as important regulators of LDR-induced immunomodulatory effects. This study provides experimental evidence to elucidate the immune enhancement induced by this process and presents a novel method for liver cancer immunotherapy.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: wangbf1680@126.com.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: f-moon@163.com.
authors.forename: Baohua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: dzj0911@126.com.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: rensong1982@gmail.com.
authors.forename: Song
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: baimh2004@126.com.
authors.forename: Minghua
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: wanglank19597@126.com.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: lzf2568@mail.xjtu.edu.cn.
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: linshuai420@stu.xjtu.edu.cn.
authors.forename: Shuai
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: xawzd@163.com.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: 428@163.com.
authors.forename: Na
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: 351249142@qq.com.
authors.forename: Pengtao
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710061, PR China. Electronic address: chubyegg007@gmail.com.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: mwl791218@126.com.
authors.forename: Weili
authors.initials: W
authors.lastname: Min
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: mahongbingxa@126.com.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology / Q000528:radiation effects; D056747:Immunomodulation / Q000528:radiation effects; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D060908:CTLA-4 Antigen; D016326:Extracellular Matrix Proteins; D051858:Forkhead Transcription Factors; D016753:Interleukin-10; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C500522:Foxp3 protein, rat
keywords: HCC; Immunomodulatory effect; Low-dose radiation; Regulatory T cell; Spleen