Tumor antigen-specific T cells for immune monitoring of dendritic cell-treated glioblastoma patients

被引:6
作者
Mueller, Isabelle [1 ]
Altherr, Dominik [1 ]
Eyrich, Matthias [2 ]
Flesch, Brigitte [3 ]
Friedmann, Kim S. [4 ]
Ketter, Ralf [5 ]
Oertel, Joachim [5 ]
Schwarz, Eva C. [4 ]
Technau, Antje [2 ]
Urbschat, Steffi [5 ]
Eichler, Hermann [1 ]
机构
[1] Univ Saarland, Med Ctr, Inst Clin Hemostaseol & Transfus Med, Ringstr 52 Gebaude 1, D-66421 Homburg, Germany
[2] Univ Wurzburg, Univ Childrens Hosp, Stem Cell Lab, Wurzburg, Germany
[3] German Red Cross Blood Serv, Immungenet HLA, Bad Kreuznach, Germany
[4] Univ Saarland, Sch Med, Ctr Integrat Physiol & Mol Med, Biophys, Homburg, Germany
[5] Univ Saarland, Sch Med, Dept Neurosurg, Homburg, Germany
关键词
CD8(+) T cells; immune monitoring; GBM peptides; dextramer staining; IFN-gamma; cancer immunotherapy; NEWLY-DIAGNOSED GLIOBLASTOMA; I CLINICAL-TRIAL; PHASE-I/II TRIAL; MALIGNANT GLIOMA; GENE-THERAPY; RECURRENT GLIOMA; SOLID TUMORS; VACCINATION; IMMUNOTHERAPY; RESPONSES;
D O I
10.1016/j.jcyt.2016.05.014
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Background aims. CD8(+)T cells are part of the adaptive immune system and, as such, are responsible for the elimination of tumor cells. Dendritic cells (DC) are professional antigen-presenting cells (APC) that activate CD8+T cells. Effector CD8(+) T cells in turn mediate the active immunotherapeutic response of DC vaccination against the aggressive glioblastoma (GBM). The lack of tumor response assays complicates the assessment of treatment success in GBM patients. Methods. A novel assay to identify specific cytotoxicity of activated T cells by APC was evaluated. Tumor antigen-pulsed DCs from HLAA*02-positive GBM patients were cultivated to stimulate autologous cytotoxic T lymphocytes (CTL) over a 12-day culture period. To directly correlate antigen specificity and cytotoxic capacity, intracellular interferon (IFN)-gamma fluorescence flow cytometrybased measurements were combined with anti-GBM tumor peptide dextramer staining. IFN-gamma response was quantified by real-time polymerase chain reaction (PCR), and selected GBM genes were compared with healthy human brain cDNA by single specific primer PCR characterization. Results. Using CTL of GBM patients stimulated with GBM lysate-pulsed DCs increased IFN-gamma messenger RNA levels, and intracellular IFN-gamma protein expression was positively correlated with specificity against GBM antigens. Moreover, the GBM peptide-specific CD8(+)T-cell response correlated with specific GBM gene expression. Following DC vaccination, GBM patients showed 10-fold higher tumor-specific signals compared with unvaccinated GBM patients. Discussion. These data indicate that GBM tumor peptide-dextramer staining of CTL in combination with intracellular IFN-gamma staining may be a useful tool to acquire information on whether a specific tumor antigen has the potential to induce an immune response in vivo.
引用
收藏
页码:1146 / 1161
页数:16
相关论文
共 72 条
[31]   Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells [J].
Kikuchi, T ;
Akasaki, Y ;
Irie, M ;
Homma, S ;
Abe, T ;
Ohno, T .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2001, 50 (07) :337-344
[32]   Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12 [J].
Kikuchi, T ;
Akasaki, Y ;
Abe, T ;
Fukuda, T ;
Saotome, H ;
Ryan, JL ;
Kufe, DW ;
Ohno, T .
JOURNAL OF IMMUNOTHERAPY, 2004, 27 (06) :452-459
[33]  
Klinghoffer RA, 2015, SCI TRANSL MED, V7
[34]   A simple, economic, time-resolved killing assay [J].
Kummerow, Carsten ;
Schwarz, Eva C. ;
Bufe, Bernd ;
Zufall, Frank ;
Hoth, Markus ;
Qu, Bin .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2014, 44 (06) :1870-1872
[35]   Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation [J].
Leisegang, Matthias ;
Engels, Boris ;
Schreiber, Karin ;
Yew, Poh Yin ;
Kiyotani, Kazuma ;
Idel, Christian ;
Arina, Ainhoa ;
Duraiswamy, Jaikumar ;
Weichselbaum, Ralph R. ;
Uckert, Wolfgang ;
Nakamura, Yusuke ;
Schreiber, Hans .
CLINICAL CANCER RESEARCH, 2016, 22 (11) :2734-2743
[36]   Targeting human melanoma neoantigens by T cell receptor gene therapy [J].
Leisegang, Matthias ;
Kammertoens, Thomas ;
Uckert, Wolfgang ;
Blankenstein, Thomas .
JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (03) :854-858
[37]   Establishment of a molecular cytogenetic analysis for native tumor tissue of meningiomas-suitable for clinical application [J].
Lerner, Cornelia ;
Ketter, Ralf ;
Linsler, Stefan ;
Henn, Wolfram ;
Oertel, Joachim ;
Urbschat, Steffi .
MOLECULAR CYTOGENETICS, 2014, 7
[38]  
Liau L M, 2000, Neurosurg Focus, V9, pe8
[39]   Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment [J].
Liau, LM ;
Prins, RM ;
Kiertscher, SM ;
Odesa, SK ;
Kremen, TJ ;
Giovannone, AJ ;
Lin, JW ;
Chute, DJ ;
Mischel, PS ;
Cloughesy, TF ;
Roth, MD .
CLINICAL CANCER RESEARCH, 2005, 11 (15) :5515-5525
[40]   HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells [J].
Liu, G ;
Ying, H ;
Zeng, G ;
Wheeler, CJ ;
Black, KL ;
Yu, JS .
CANCER RESEARCH, 2004, 64 (14) :4980-4986