Low-dose Cyclophosphamide Treatment Impairs Regulatory T Cells and Unmasks AFP-specific CD4+ T-cell Responses in Patients With Advanced HCC

被引:101
作者
Greten, Tim F. [1 ,2 ]
Ormandy, Lars A. [1 ,3 ]
Fikuart, Annika [1 ,2 ]
Hoechst, Bastian [1 ,2 ]
Henschen, Sylvana [1 ,2 ]
Hoerning, Monique [1 ]
Manns, Michael P. [1 ]
Korangy, Firouzeh [1 ,2 ]
机构
[1] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany
[2] Twincore Ctr Expt & Clin Infect Res, Hannover, Germany
[3] Univ Gottingen, Dept Forens Med, Gottingen, Germany
关键词
immunotherapy; suppressor cells; tumor antigen; cancer vaccine; HEPATOCELLULAR-CARCINOMA PATIENTS; ANTITUMOR IMMUNE-RESPONSE; PERIPHERAL-BLOOD; IMMUNOTHERAPY; SURVIVAL; INCREASE; CANCER; LIVER; FOXP3;
D O I
10.1097/CJI.0b013e3181bb499f
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Immunotherapy represents a potential therapeutic option for patients with hepatocellular carcinoma (HCC). However, CD4(+)CD25(+)Foxp(+) regulatory T cells, which suppress potential antigen-specific T-cell responses, are increased in patients with HCC and might impair the effect of an immune-based therapeutic approach. In this study, we demonstrate that depletion of regulatory T cells in vitro unmasks alpha-fetoprotein-specific T-cell responses in HCC patients. On the basis of these results, we performed a clinical trial, in which 13 patients with advanced HCC ineligible for any other type of treatment were treated with 150, 250, or 350 mg/m(2) cyclophosphamide on day 1 and 29 to suppress regulatory T cells in these patients (NCT00396682). The primary end point of this trial was regulatory T-cell number and function. Low-dose cyclophosphamide treatment (150 and 250 mg/m(2)) induced a decrease in the absolute and relative frequency of CD4(+)CD25(+)Foxp(+) regulatory T cells in peripheral blood on days 8 and 29. Suppressor function of regulatory T cells was impaired after treatment of patients with 250 mg/m(2) on days 8 and 21. Finally, alpha-fetoprotein-specific T-cell responses were unmasked in 6/13 treated patients. In summary, systemic treatment of HCC patients with low-dose cyclophosphamide decreases the frequency and suppressor function of circulating CD4(+)CD25(+)Foxp(+) regulatory T cells in peripheral blood and could be used in combination with immunotherapeutic approaches in HCC.
引用
收藏
页码:211 / 218
页数:8
相关论文
共 26 条
[11]   Immunotherapy of HCC [J].
Greten, Tim F. ;
Manns, Michael P. ;
Korangy, Firouzeh .
REVIEWS ON RECENT CLINICAL TRIALS, 2008, 3 (01) :31-39
[12]   A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells [J].
Hoechst, Bastian ;
Ormandy, Lars A. ;
Ballmaier, Matthias ;
Lehner, Frank ;
Krueger, Christine ;
Manns, Michael P. ;
Greten, Tim F. ;
Korangy, Firouzeh .
GASTROENTEROLOGY, 2008, 135 (01) :234-243
[13]   Control of regulatory T cell development by the transcription factor Foxp3 [J].
Hori, S ;
Nomura, T ;
Sakaguchi, S .
SCIENCE, 2003, 299 (5609) :1057-1061
[14]   Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma [J].
Korangy, F ;
Ormandy, LA ;
Bleck, JS ;
Klempnauer, A ;
Wilkens, L ;
Manns, MP ;
Greten, TF .
CLINICAL CANCER RESEARCH, 2004, 10 (13) :4332-4341
[15]   Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: A pilot study of safety, feasibility, and immune activation [J].
Laheru, Dan ;
Lutz, Eric ;
Burke, James ;
Biedrzycki, Barbara ;
Solt, Sara ;
Onners, Beth ;
Tartakovsky, Irena ;
Nemunaitis, John ;
Le, Dung ;
Sugar, Elizabeth ;
Hege, Kristen ;
Jaffee, Elizabeth .
CLINICAL CANCER RESEARCH, 2008, 14 (05) :1455-1463
[16]   CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells [J].
Liu, Weihong ;
Putnam, Amy L. ;
Xu-yu, Zhou ;
Szot, Gregory L. ;
Lee, Michael R. ;
Zhu, Shirley ;
Gottlieb, Peter A. ;
Kapranov, Philipp ;
Gingeras, Thomas R. ;
Fazekas de St Groth, Barbara ;
Clayberger, Carol ;
Soper, David M. ;
Ziegler, Steven F. ;
Bluestone, Jeffrey A. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (07) :1701-1711
[17]   Sorafenib in advanced hepatocellular carcinoma [J].
Llovet, Josep M. ;
Ricci, Sergio ;
Mazzaferro, Vincenzo ;
Hilgard, Philip ;
Gane, Edward ;
Blanc, Jean-Frederic ;
Cosme de Oliveira, Andre ;
Santoro, Armando ;
Raoul, Jean-Luc ;
Forner, Alejandro ;
Schwartz, Myron ;
Porta, Camillo ;
Zeuzem, Stefan ;
Bolondi, Luigi ;
Greten, Tim F. ;
Galle, Peter R. ;
Seitz, Jean-Francois ;
Borbath, Ivan ;
Haussinger, Dieter ;
Giannaris, Tom ;
Shan, Minghua ;
Moscovici, Marius ;
Voliotis, Dimitris ;
Bruix, Jordi .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (04) :378-390
[18]   Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide [J].
Lutsiak, MEC ;
Semnani, RT ;
De Pascalis, R ;
Kashmiri, SVS ;
Schlom, J ;
Sabzevari, H .
BLOOD, 2005, 105 (07) :2862-2868
[19]  
Machiels JPH, 2001, CANCER RES, V61, P3689
[20]  
Motoyoshi Y, 2006, ONCOL REP, V16, P141