Identification of Tumor-Associated Autoantigens With SEREX

Türeci, Özlem; Usener, Dirk; Schneider, Sandra; Şahin, Uğur

doi:10.1385/1-59259-862-5:137

Cited by 25 publications

(28 citation statements)

References 17 publications

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“…Our approach utilizes the added dimension of the changes in O-glycosylation that occur in cancer. This is in contrast to other methods used to identify specific targets for autoantibodies that do not allow for the detection of antibodies to epitopes resulting from cancer-associated post-translational modifications [1,10,14]. …”

Section: Introductionmentioning

confidence: 98%

Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis

et al. 2011

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IntroductionDetection of serum biomarkers for early diagnosis of breast cancer remains an important goal. Changes in the structure of O-linked glycans occur in all breast cancers resulting in the expression of glycoproteins that are antigenically distinct. Indeed, the serum assay widely used for monitoring disease progression in breast cancer (CA15.3), detects a glycoprotein (MUC1), but elevated levels of the antigen cannot be detected in early stage patients. However, since the immune system acts to amplify the antigenic signal, antibodies can be detected in sera long before the antigen. We have exploited the change in O-glycosylation to measure autoantibody responses to cancer-associated glycoforms of MUC1 in sera from early stage breast cancer patients.MethodsWe used a microarray platform of 60mer MUC1 glycopeptides, to confirm the presence of autoantibodies to cancer associated glycoforms of MUC1 in a proportion of early breast cancer patients (54/198). Five positive sera were selected for detailed definition of the reactive epitopes using on chip glycosylation technology and a panel of glycopeptides based on a single MUC1 tandem repeat carrying specific glycans at specific sites. Based on these results, larger amounts of an extended repertoire of defined MUC1 glycopeptides were synthesised, printed on microarrays, and screened with sera from a large cohort of breast cancer patients (n = 395), patients with benign breast disease (n = 108) and healthy controls (n = 99). All sera were collected in the 1970s and 1980s and complete clinical follow-up of breast cancer patients is available.ResultsThe presence and level of autoantibodies was significantly higher in the sera from cancer patients compared with the controls, and a highly significant correlation with age was observed. High levels of a subset of autoantibodies to the core3MUC1 (GlcNAcβ1-3GalNAc-MUC1) and STnMUC1 (NeuAcα2,6GalNAc-MUC1) glycoforms were significantly associated with reduced incidence and increased time to metastasis.ConclusionsAutoantibodies to specific cancer associated glycoforms of MUC1 are found more frequently and at higher levels in early stage breast cancer patients than in women with benign breast disease or healthy women. Association of strong antibody response with reduced rate and delay in metastases suggests that autoantibodies can affect disease progression.

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Section: Introductionmentioning

confidence: 98%

Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis

et al. 2011

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“…Also included are two previously described cancer testis antigens, NY-ESO-1, which has previously been shown to induce autoantibodies in NSCLC,21 22 and CAGE, which has been described as capable of inducing an autoantibody response in gastric,23 24 pancreatic,25 and some lung cancers 21 23. The final antigen in the panel is a recently identified protein GBU4–5, which was identified using SEREX technologies26 and described in a previous publication 24. GBU4–5 encodes a DEAD-box domain (like CAGE), but until 2003 had not been described as eliciting an autoantibody response.…”

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confidence: 99%

Autoantibodies in lung cancer: possibilities for early detection and subsequent cure

Chapman

Murray

McElveen

et al. 2008

Thorax

204

181

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“…We and other groups also noted that the majority of Ags identified by SEREX are autoantigens, which might be due to the liberation of cytoplasmic proteins during necrotic cell death that frequently occurs during tumor growth (32)(33)(34)(35). One of these autoantigens in which high-titer Abs have been detected in the sera of all patients with RCC has been GOLGA4 (32).…”

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confidence: 87%

Concomitant Tumor and Autoantigen Vaccination Supports Renal Cell Carcinoma Rejection

Herbert

Haferkamp²,

Schmitz‐Winnenthal³

et al. 2010

The Journal of Immunology

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Efficient tumor vaccination frequently requires adjuvant. Concomitant induction of an autoimmune response is discussed as a means to strengthen a weak tumor Ag-specific response. We asked whether the efficacy of dendritic cell (DC) vaccination with the renal cell carcinoma Ags MAGE-A9 (MAGE9) and G250 could be strengthened by covaccination with the renal cell carcinoma autoantigen GOLGA4. BALB/c mice were vaccinated with DC loaded with MHC class I-binding peptides of MAGE9 or G250 or tumor lysate, which sufficed for rejection of low-dose RENCA-MAGE9 and RENCA-G250 tumor grafts, but only retarded tumor growth at 200 times the tumor dose at which 100% of animals will develop a tumor. Instead, 75–100% of mice prevaccinated concomitantly with Salmonella typhimurium transformed with GOLGA4 cDNA in a eukaryotic expression vector rejected 200 times the tumor dose at which 100% of animals will develop tumor. In a therapeutic setting, the survival rate increased from 20–40% by covaccination with S. typhimurium-GOLGA4. Autoantigen covaccination significantly strengthened tumor Ag-specific CD4+ and CD8+ T cell expansion, particularly in peptide-loaded DC-vaccinated mice. Covaccination was accompanied by an increase in inflammatory cytokines, boosted IL-12 and IFN-γ expression, and promoted a high tumor Ag-specific CTL response. Concomitant autoantigen vaccination also supported CCR6, CXCR3, and CXCR4 upregulation and T cell recruitment into the tumor. It did not affect regulatory T cells, but slightly increased myeloid-derived suppressor cells. Thus, tumor cell eradication was efficiently strengthened by concomitant induction of an immune response against a tumor Ag and an autoantigen expressed by the tumor cell. Activation of autoantigen-specific Th cells strongly supports tumor-specific Th cells and thereby CTL activation.

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Identification of Tumor-Associated Autoantigens With SEREX

Cited by 25 publications

References 17 publications

Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis

Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis

Autoantibodies in lung cancer: possibilities for early detection and subsequent cure

Concomitant Tumor and Autoantigen Vaccination Supports Renal Cell Carcinoma Rejection

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