Hodgkin’s lymphoma RNA-transfected dendritic cells induce cancer/testis antigen-specific immune responses

Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097, Halle, Germany.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 03/2012; 61(10):1769-79. DOI: 10.1007/s00262-012-1239-z
Source: PubMed


Cytotoxic T lymphocytes (CTL) can kill Hodgkin's lymphoma (HL) cells, and CTL have been used for the treatment of Epstein-Barr virus (EBV)-positive HL. For patients with EBV-negative HL, this strategy cannot be employed and alternative target structures have to be defined. In order to establish a system for the stimulation of HL-reactive T cells, we used dendritic cells (DC) as antigen-presenting cells for autologous T cells and transfected these DC with RNA from established HL cell lines. After stimulation of peripheral blood mononuclear cells (PBMC) with RNA-transfected DC, we analyzed the reactivity of primed PBMC by interferon gamma enzyme-linked immunospot. Our results suggest the presence of antigens with expression in HL cell lines and recognition of these antigens in combination with DC-derived human leukocyte antigen molecules. By the analysis of Gene Expression Omnibus microarray data sets from HL cell lines and primary HL samples in comparison with testis and other normal tissues, we identified HL-associated cancer testis antigens (CTA) including the preferentially expressed antigen in melanoma (PRAME). After stimulation of PBMC with RNA-transfected DC, we detected PRAME-reactive T cells. PRAME and other HL-associated CTA might be targets for HL-specific immune therapy or for the monitoring of HL-directed immune responses.

Download full-text


Available from: Alexander Emmer, Aug 25, 2014
37 Reads
  • Source
    • "HL high sensitivity to radio- and chemotherapy is known for a long time and has led to the development of highly effective treatment regimens (reviewed in (60)). H2A.Bbd is specifically overexpressed in HL cell lines and in HL cells in vivo (17) and might be involved in the high success of radio- and chemotherapy for treatment of these patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone variants play an important role in shaping the mammalian epigenome and their aberrant expression is frequently observed in several types of cancer. However, the mechanisms that mediate their function and the composition of the variant-containing chromatin are still largely unknown. A proteomic interrogation of chromatin containing the different H2A variants macroH2A.1.2, H2A.Bbd and H2A revealed a strikingly different protein composition. Gene ontology analysis reveals a strong enrichment of splicing factors as well as components of the mammalian replisome in H2A.Bbd-containing chromatin. We find H2A.Bbd localizing transiently to sites of DNA synthesis during S-phase and during DNA repair. Cells that express H2A.Bbd have a shortened S-phase and are more susceptible to DNA damage, two phenotypes that are also observed in human Hodgkin's lymphoma cells that aberrantly express this variant. Based on our experiments we conclude that H2A.Bbd is targeted to newly synthesized DNA during replication and DNA repair. The transient incorporation of H2A.Bbd may be due to the intrinsic instability of nucleosomes carrying this variant or a faster chromatin loading. This potentially leads to a disturbance of the existing chromatin structure, which may have effects on cell cycle regulation and DNA damage sensitivity.
    Nucleic Acids Research 04/2014; 42(10). DOI:10.1093/nar/gku303 · 9.11 Impact Factor
  • Source
    • "Most of our knowledge about PRAME comes from the analysis of solid tumors or leukemia cells. All HL cell lines tested have higher expression of PRAME in comparison to normal blood cells [19]. HL cells with relatively low expression of PRAME (cell line L-540) show increased expression of PRAME after treatment with the de-methylating agent 5′-azacytidine [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prognosis for patients with Hodgkin lymphoma (HL) has improved in recent decades. On the other hand, not all patients can be cured with the currently established therapy regimes and this therapy is associated with several adverse late effects. Therefore it is necessary to develop new therapy strategies. After treatment of L-540 HL cells with 5'-azacytidine (5AC), we observed increased expression of the preferentially expressed antigen in melanoma (PRAME). In addition, we detected an increased resistance of 5AC-treated cells against cytotoxic drugs. We analyzed the influence of PRAME on cell survival of HL cells by knocking down PRAME in the chemotherapy resistant cell line L-428, a cell line that express PRAME at a high level. After knock-down of PRAME using vector based RNA interference we observed increased sensitivity for cisplatin, etoposide and retinoic acid. DNA microarray analysis of HL cells after PRAME knock-down indicated regulation of several genes including down-regulation of known anti-apoptotic factors. Increased retinoic acid signaling in these cells was revealed by increased expression of the retinoic acid metabolizing cytochrome P450 (CYP26B1), a transcriptional target of retinoic acid signaling. Our data suggest that PRAME inhibits retinoic acid signaling in HL cells and that the knock-down of PRAME might be an interesting option for the development of new therapy strategies for patients with chemo-resistant HL.
    PLoS ONE 02/2013; 8(2):e55897. DOI:10.1371/journal.pone.0055897 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immune therapy of cancer is a rapidly evolving field, with long-deserved successes now finally achieved. As new pathways triggered by the immune synapsis are elucidated, and new molecules responsible for immune checkpoints are being discovered, it is becoming clear that vaccination against a single antigen aided by non-specific immune stimulation is not sufficient for an efficient, long term, immune response. Though lymphoma is a highly curable malignancy, there is still a subset of patients that is at very high risk of disease relapse even after successfully completing chemotherapy or a stem cell transplant. Patients with minimal residual disease are particularly suitable for vaccination. Over the past 3 decades, the classic model of lymphoma-specific idiotype vaccine has evolved and recent data on vaccination with nonspecific oligodeoxynucleotides has provided very encouraging results. Furthermore, the introduction of checkpoint blockade via agonist or antagonist monoclonal antibodies holds the promise of significant improvement in the efficacy of future vaccines. What follows is a brief summary of the historical highlights in lymphoma immunotherapy as well as an update on the most recently published clinical trials and a look at future developments.
    Current Oncology Reports 07/2012; 14(5):433-40. DOI:10.1007/s11912-012-0255-7 · 2.89 Impact Factor
Show more

Similar Publications