Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin

Mensdorff‐Pouilly, Silvia von; Verstraeten, A.A.; Kenemans, P.; Snijdewint, F.G.M.; Kok, A.; Kamp, Gerard J. van; Paul, Marinus A.; Diest, Paul J. van; Meijer, Sybren L.; Hilgers, J.

doi:10.1200/jco.2000.18.3.574

Cited by 198 publications

(161 citation statements)

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“…Overexpression of tumour antigens or expression of cryptic antigens following structural modification can lead to an improper immune reaction against this protein (von Mensdorff-Pouilly et al, 2000). Such a phenomenon might explain the presence of autoantibodies to endostatin in our patients; even so, endostatin may be expressed mostly by tumour-associated stromal cells.…”

Section: Discussionmentioning

confidence: 85%

“…Autoantibodies are frequently observed in the sera of patients with malignancies and their titres have been correlated to patients' survival or other clinicopathological parameters (Soussi, 2000;von Mensdorff-Pouilly et al, 2000). Cancer-related autoimmunity often appears to be directed against mutant forms of proteins or is associated with the overexpression of autoantigens in autologous tumour cells (Boon and Old, 1997;Soussi, 2000).…”

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confidence: 99%

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Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

et al. 2006

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Circulating autoantibodies to self-antigens overexpressed by cancer cells are common in cancer patients. As specific proteins are expressed during neoangiogenesis, a similar phenomenon might occur with particular antigens of tumour vessels. Collagen XVIII, from which endostatin is cleaved, is highly expressed in the perivascular basement membrane of tumour-associated blood vessels and autoantibodies to endostatin have been reported in cancer patients. The present study analyses the incidence of naturally occurring autoantibodies to endostatin in the sera of breast cancer patients and their relation to endostatin serum levels and patient clinical outcome. Serum samples from 36 patients with localised breast cancer and 59 patients with a fully documented history of metastatic breast cancer were used. The immunoreactivity of serum samples was tested against purified recombinant human endostatin and endostatin levels were determined by immunoassay. We could detect anti-endostatin antibodies in the sera of 66% of the patients with localised disease and 42% of the patients with metastatic disease (P ¼ 0.03). There was no correlation between the presence of antibodies to endostatin and circulating levels of endostatin. The detection of autoantibodies to endostatin was associated with better prognosis in metastatic breast cancer patients (median survival time: 20 vs 8 months, P ¼ 0.03), as was the presence of low levels of serum endostatin (median survival time: 20 vs 9 months, P ¼ 0.007). These results show that a natural immune reaction against endostatin can occur in breast cancer patients. This could have important therapeutic implications with regard to endostatin therapy and raises the question of a possible role of this humoral reaction against endostatin in the neoplastic process.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

et al. 2006

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“…These circulating antibodies are associated with a good prognosis [17]. Moreover, a report that non-MHC-restricted cytotoxic T-cells could be isolated that recognized an epitope in the TR sequence of MUC1, which is masked in the normal mucin, suggested that cellular immune responses may also be induced [18].…”

Section: Introductionmentioning

confidence: 99%

Recombinant MUC1 mucin with a breast cancer-like O-glycosylation produced in large amounts in Chinese-hamster ovary cells

Bäckström

Link

Olson

et al. 2003

Biochemical Journal

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We have developed an expression system for the production of large quantities of recombinant MUC1 mucin in CHO-K1 (Chinese-hamster ovary K1) cells. The extracellular part of human MUC1, including 16 MUC1 tandem repeats, was produced as a fusion protein with murine IgG Fc, with an intervening enterokinase cleavage site for the removal of the Fc tail. Stable MUC1-IgG-producing CHO-K1 clones were generated and were found to secrete MUC1-IgG into the culture medium. After adaptation to suspension culture in protein-free medium in a bioreactor, the fusion protein was secreted in large quantities (100 mg/l per day) into the culture supernatant. From there, MUC1 could be purified to homogeneity using a two-step procedure including enterokinase cleavage and ion-exchange chromatography. Capillary liquid chromatography MS of released oligosaccharides from CHO-K1-produced MUC1 identified the main O-glycans as Galβ1-3GalNAc (core 1) and mono-and disialylated core 1. The glycans occupied on average 4.3 of the five potential O-glycosylation sites in the tandem repeats, as determined by nano-liquid chromatography MS of partially deglycosylated Clostripain-digested protein. A very similar O-glycan profile and site occupancy was found in MUC1-IgG produced in the breast carcinoma cell line T47D, which has O-glycosylation typical for breast cancer. In contrast, MUC1-IgG produced in another breast cancer cell line, MCF-7, showed a more complex pattern with both core 1-and core 2-based O-glycans. This is the first reported production of large quantities of recombinant MUC1 with a breast cancer-like O-glycosylation that could be used for the immunotherapy of breast cancer.

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“…5 There have been reports of humoral and cellular immune responses to MUC1 in multiparous women and in cancer patients, 6 with the presence of a humoral response reportedly being a good prognostic factor for outcome in breast cancer patients. 7 These data together with the high level of expression in tumour cells have led to a focus on MUC1 as a potential target for tumour immunotherapy.…”

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Responses of human T cells to peptides flanking the tandem repeat and overlapping the signal sequence of MUC1

Correa

Plunkett

Coleman

et al. 2005

Intl Journal of Cancer

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The epithelial mucin MUC1 is one of the few tumour‐associated antigens identified for breast cancer. Several MUC1‐derived peptides binding HLA‐A*0201 molecules have been identified that correspond to sequences outside the tandem repeat. Immunisation with some of these peptides induces protective antitumour immunity in mice. Another HLA‐A*0201‐binding peptide has been identified in a human system. We have evaluated the CD8+ T‐cell responses to all these peptides using peripheral blood lymphocytes from breast cancer patients and normal donors. Specific CD8+ T‐cell responses could be generated in vitro against some of these peptides but only after several rounds of in vitro restimulation, and they did not recognise human cells endogenously expressing the antigen. Nevertheless, T cells recognised by HLA‐A*0201 tetramers carrying a peptide from the signal sequence (LLLLTVLTV) could be detected in the peripheral blood of some HLA‐A*0201+ breast cancer patients but not in healthy adults. This peptide is the only one of those tested which was identified in the human system, and the results emphasize the potential problems involved in translation of data from laboratory animal models to the human system. © 2005 Wiley‐Liss, Inc.

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Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin

Cited by 198 publications

References 57 publications

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

Recombinant MUC1 mucin with a breast cancer-like O-glycosylation produced in large amounts in Chinese-hamster ovary cells

Responses of human T cells to peptides flanking the tandem repeat and overlapping the signal sequence of MUC1

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