Cancer/Testis Genes in Multiple Myeloma: Expression Patterns and Prognosis Value Determined by Microarray Analysis

Institute of Research in Biotherapy, Centre Hospitalier Universitaire Montpellier, Montpellier, France.
The Journal of Immunology (Impact Factor: 4.92). 04/2007; 178(5):3307-15. DOI: 10.4049/jimmunol.178.5.3307
Source: PubMed


Cancer-testis (CT) Ags are expressed in testis and malignant tumors but rarely in nongametogenic tissues. Due to this pattern, they represent attractive targets for cancer vaccination approaches. The aims of the present study are: 1) to assess the expression of CT genes on a pangenomic base in multiple myeloma (MM); 2) to assess the prognosis value of CT gene expression; and 3) to provide selection strategies for CT Ags in clinical vaccination trials. We report the expression pattern of CT genes in purified MM cells (MMC) of 64 patients with newly diagnosed MM and12 patients with monoclonal gammopathy of unknown significance, in normal plasma cell and B cell samples, and in 20 MMC lines. Of the 46 CT genes interrogated by the Affymetrix HG-U133 set arrays, 35 are expressed in the MMC of at least one patient. Of these, 25 are located on chromosome X. The expression of six CT genes is associated with a shorter event-free survival. The MMC of 98% of the patients express at least one CT gene, 86% at least two, and 70% at least three CT genes. By using a set of 10 CT genes including KM-HN-1, MAGE-C1, MAGE-A3/6/12, MAGE-A5, MORC, DDX43, SPACA3, SSX-4, GAGE-1-8, and MAGE-C2, a combination of at least three CT genes-desirable for circumventing tumor escape mechanisms-is obtained in the MMC of 67% of the patients. Provided that the immunogenicity of the products of these 10 CT genes is confirmed, gene expression profiling could be useful in identifying which CT Ags could be used to vaccinate a given patient.

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    • "These antigens represent potential markers for minimal residual disease (MRD) after ASCT and could also be used to target myeloma cells remaining in the patients' BM after standard therapy. In addition, in MM, expression of CT antigens has been shown to be strongly correlated to the clinical outcome; that is, the presence of CT antigens expression has been linked to shorter survival [127]. Baseline expression frequencies, measured by RT-PCR, determined MAGE-C1/CT7 as the most frequently detected antigen, possibly perform a gatekeeper function for the other antigens examined. "
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    ABSTRACT: Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results.
    Full-text · Article · May 2012 · Clinical and Developmental Immunology
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    • "solid tumours (Simpson et al, 2005), but there are increasing reports of CTAs being expressed in haematological malignancies , such as multiple myeloma (Pellat-Deceunynck et al, 2000; Lim et al, 2001; Goodyear et al, 2005; Jungbluth et al, 2005; van Rhee et al, 2005), lymphomas (Eichmuller et al, 2003; Xie et al, 2003) and myeloid malignancies (Adams et al, 2002; Zhang et al, 2003). A particularly relevant gene expression profiling study recently reported transcripts of multiple CTAs in myeloma tumour cells (Condomines et al, 2007). Other studies have also reported the presence of cytotoxic T cells (CTLs) to CTAs, such as NY-ESO-1 and Sp17, in multiple myeloma patients, suggesting the presence of spontaneous immunity to these CTAs (Goodyear et al, 2005; van Rhee et al, 2005). "
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    ABSTRACT: The identification of immunogenic cancer testis antigens (CTAs) as immunotherapeutic targets represents one approach to improve treatment options for diffuse large B-cell lymphoma (DLBCL). We previously identified PASD1 [PAS (Per ARNT Sim) domain containing 1 (PASD1)], a DLBCL-associated CTA that was expressed in a range of hematopoietic malignancies. The aim of the present study was to investigate the presence of a cytotoxic T-cell (CTL) response to PASD1 in DLBCL patients. A significant gamma-interferon (IFN) release was detected in 21/29 HLA-A*0201-positive DLBCL patients (18 de novo DLBCL, two transformed DLBCL and one T-cell rich B-cell lymphoma) following short-term culture of their peripheral blood mononuclear cells stimulated with five HLA-A*0201-restricted PASD1 peptides. No significant responses were detected in 21 HLA-A*0201-negative DLBCL patients (12 de novo DLBCL, seven transformed DLBCL, two T-cell rich B-cell lymphoma) or six normal subjects. CTL cell lines were able to lyse PASD1-positive tumour cells in a major histocompatibility complex-Class I dependent manner. The presence of a gamma-IFN response correlated with PASD1 protein expression in the tumour cells in 12/15 cases studied. This is the first report of a CTL response to a CTA in DLBCL. Our results provide additional valuable evidence supporting PASD1 as a potential immunotherapeutic target for the treatment of DLBCL and other malignancies.
    Full-text · Article · Jul 2009 · British Journal of Haematology
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    • "Although KM-HN-1 has previously been identified as a cancer/testis antigen, the study of KM-HN-1 has mainly been limited to mRNA expression level analyses using several cancer tissues and cell lines (Monji et al., 2004; Condomines et al., 2007). KM-HN-1 has been shown to localize to the nucleus in interphase cells and chromosomes in mitotic cells, but the characterization of this protein at the protein level has not been addressed yet. "
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    ABSTRACT: KM-HN-1 is a C-terminal coiled-coil domain containing protein previously referred to as image clone MGC33607. This protein has been previously identified as a cancer/testis antigen and reported as nuclear and chromatin localizing protein. We raised polyclonal antisera with the GST fusion protein and identified them as a 105 kDa protein. Motif analysis showed that this protein harbors the leucine zipper motif in internal 1/3 region and the coiled-coil domain in the C-terminal region. Using the full length and various deletion mutants, we determined the motif that governs the subcellular localization of KM-HN-1. Immunofluorescence staining of the endogenous KM-HN-1 and various kinds of GFP-tagged KM-HN-1 revealed that KM-HN-1 localizes to the centrosomes as well as nucleus. The centrosomal localization-determining region of this protein is C-terminal coiled-coil domain in which the leucine zipper motif and the nuclear export signal (NES) harbor.
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