MAGE-C1/CT7 is the dominant cancer-testis antigen targeted by humoral immune responses in patients with multiple myeloma

Curioni-Fontecedro, Alessandra; Knights, Ashley; Tinguely, Marianne; Nuber, Natko; Schneider, Celine; Thomson, Christopher W.; Boehmer, Lotta von; Bossart, Walter; Pahlich, Steffen; Gehring, Heinz; Moch, Holger; Renner, Christoph; Zippelius, Alfred

doi:10.1038/leu.2008.43

Cited by 22 publications

(19 citation statements)

References 7 publications

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“…We detected high-titered CT7-specific serum IgG in 2 of 48 patients (on Western blots loaded with CT7 + tumor cell lysates). This low incidence of CT7-specific humoral response in melanoma patients is in contrast to our previous study on multiple myeloma patients (34). This discrepancy could be due to surgical removal of melanoma, which often results in the disappearance of tumor-specific antibodies, as was shown for NY-ESO-1 (35).…”

Section: Ct7-specific Cd4 + T-cell Clones Recognize Naturally Processcontrasting

confidence: 54%

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Nuber

Curioni-Fontecedro

Matter

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7 + ) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4 + T-cell responses were detected in three patients (11.5%). These CT7-specific CD4 + T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA − memory CD4 + T-cell pool. Additional CT7-specific memory CD4 + T-cell responses were detected in CT7 + melanoma patients after depletion of CD4 + CD25high Treg cells showing that Treg cells impact on CT7-specific CD4 + T cells in melanoma patients. CT7-specific CD4 + T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.cancer/testis antigens | T-cell response

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Section: Ct7-specific Cd4 + T-cell Clones Recognize Naturally Processcontrasting

confidence: 54%

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Nuber

Curioni-Fontecedro

Matter

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Further work is required to look at T-cell responses to other CTAgs, particularly MAGE-C1, which is widely expressed in myeloma, although no T-cell epitopes from MAGE-C1 have been described to date. 55 Our data indicate that cancer testis antigens represent an important target for future immunotherapeutic intervention in MM. .…”

Section: Discussionmentioning

confidence: 99%

Differential pattern of CD4+ and CD8+ T-cell immunity to MAGE-A1/A2/A3 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma

Goodyear

Pratt

McLarnon

et al. 2008

Blood

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The factors that determine progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma are unclear but may include the breakdown of immune surveillance. Cancer testis antigens (CTAgs) are expressed by the majority of myelomas and MGUS tumors and are a potential immune target. We have characterized CD4 ؉ and CD8 ؉ T-cell immune responses to MAGE-A1/ A2/A3 in these patients. CD4 ؉ T-cell immunity to MAGE proteins is stronger and more frequent in MGUS compared with myeloma with a predominantly CD45RA ؊ CCR7 ؊ effector memory profile and cytotoxicity against MAGE-positive cell lines. In contrast CD8 ؉ T-cell immune responses were present almost exclusively in patients with multiple myeloma, correlating with disease, with a CD45RA ؉ CCR7 ؊ memory phenotype, localizing poorly to the bone marrow but were able to lyse myeloma cell lines in vitro. This suggests that the CD4 ؉ CTAg-specific immune response may play a role in controlling tumor growth, whereas the efficacy of the CD8 ؉ T-cell response appears to be limited in vivo. Despite this, patients with evidence of a CTAg-specific immune response had a 53% reduction in mortality over a median follow-up of 4 years. These findings have important implications for clinical approaches to CTAg-specific immunotherapy in patients with cancer. (Blood. 2008;112:3362-3372) IntroductionMultiple myeloma (MM) is a malignant disease of bone marrow plasma cells and remains incurable with current chemotherapy regimens. [1][2][3] Although allogeneic stem cell transplantation is associated with significant morbidity and mortality, a graft-versus-myeloma effect has clearly been demonstrated, 4,5 and tumor-specific immunotherapy offers potential in the management of this disease. 6 CTAgs are a family of proteins whose expression is restricted to spermatogenic germ cells, 7 and more than 50 CTAg genes exhibit mRNA expression in testis with minimal expression in adult somatic cells. 8,9 CTAg expression is observed in a wide variety of malignancies including melanoma and epithelial tumors. T-cell tolerance to CTAg peptides appears incomplete and functional T-cell responses may be generated as a consequence of CTAg expression in tumor cells. 10 Expression of several CTAg proteins, including MAGE and NY-ESO, has been described in malignant plasma cells from patients with MM as well as transformed cell lines. [11][12][13][14][15][16][17][18] CTAg expression is detected most commonly in patients with advanced disease but is also found in a significant proportion of patients with MGUS. 15 Recently, aberrant expression of CTAgs has been shown to be a negative prognostic marker for MM 17,19 and to be associated with a proliferative subset of tumor cells. 15 There is also a correlation in MM 18 and in certain solid tumors 20 between the age of the patient and the number of expressed CTAgs. The mechanisms that underlie this expression are unclear but are at least partially related to demethylation of gene promoter sequences. 7 CTAgs have been the target for several ...

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“…Myeloma is a malignancy which is thought to be controlled, at least © F e r r a t a S t o r t i F o u n d a t i o n to a certain extent, by the adaptive immune system, a view which is supported by the fact that the therapeutic effect of allogeneic stem cell transplantation is partly mediated by donor-derived T cells and that infusions of donor T cells are capable of inducing remission in relapsed MM patients. 42,43 We and others have recently shown that spontaneous antibody and T-cell immunity against MAGE-A3 and MAGE-C1/CT7 is present in patients with MM 10,[44][45][46] and that the presence of such immunity might be associated with an improved prognosis. 44 Our finding that immune responses against CT antigens are induced by allogeneic stem cell transplantation 10 suggests that these tumor antigens might indeed represent natural targets for donor-derived allo-immune or even spontaneous anti-myeloma immune responses.…”

Section: Discussionmentioning

confidence: 99%

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Atanackovic¹,

Hildebrandt²,

Jadczak³

et al. 2009

Haematologica

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BackgroundMultiple myeloma is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of cancer-testis genes in myeloma remains poorly understood. Design and MethodsWe performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interferencebased gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing. ResultsWe show that the investigated genes are not involved in regulating cell proliferation or adhesion; however, they play an important role in promoting the survival of myeloma cells. Accordingly, knock-down of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies. ConclusionsCancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might, therefore, represent attractive targets for novel myeloma-specific therapies.Key words: cancer-testis antigens, gene function, RNAi, apoptosis, tumor immunology, multiple myeloma, stem cell transplantation.Citation: Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, promote the survival of multiple myeloma cells. Haematologica 2010;95:785-793. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

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MAGE-C1/CT7 is the dominant cancer-testis antigen targeted by humoral immune responses in patients with multiple myeloma

Cited by 22 publications

References 7 publications

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Differential pattern of CD4+ and CD8+ T-cell immunity to MAGE-A1/A2/A3 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

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