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Pre-existing T-cell immunity against mucin-1 in breast cancer patients and healthy volunteers

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Abstract

Purpose: There is evidence that some tumor patients are able to generate tumor-associated antigen (TAA)-specific T-cell immunity spontaneously. However, little is understood about the existence and nature of self-reactive T-cells that recognize TAA in healthy donors (HD). Methods: Human mucin (MUC-1), a highly glycosylated transmembrane protein, is a well characterized TAA expressed by epithelial tumors. We compared endogenous MUC-1-specific T-cell immunity of breast cancer patients (BCP) and healthy volunteers using two MUC-1-derived HLA-A*0201-restricted peptides (MUC-1950–958, MUC-112–20). Antigen-dependent interferon (IFN)-γ and Granzyme B expression of T-cells were analysed by a reverse transcription-polymerase chain reaction (qRT-PCR)-based assay. Results: A 32% of BCP and 43% of healthy volunteers revealed pre-existent CD8+ T-cells specific for MUC-1950–958 but not for MUC-112–20. In patients, MUC-1-specific T-cells have been detected mainly in early stage disease prior adjuvant therapy. Those T-cells showed MUC-1-dependent IFN-γ production after short-term stimulation but no clear Granzyme B expression. However, after repetitive in vitro stimulations using peptide-pulsed CD40-stimulated B-cell lines as autologous antigen presenting cells (APC) T-cell lines exhibited lytic capacity against HLA-A*0201+/MUC-1+ tumor cells. Conclusion: MUC-1950–958 is a dominant tumor antigen against which CD8+ T-cells were found frequently in BCP as well as in HD. Until now, this was only known for MelanA/MART-1. In contrast to previous reports, MUC-1-specific immunity was not linked to gender or number of pregnancies in women. Whether MUC-1950–958-related immunity highlights a yet unknown cross-reactivity in HD remains unclear. The presence of MUC-1-specific T-cells in some BCP may reflect a balance between immune tolerance and immune defence during aetiopathology.

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Fig. 1

Abbreviations

APC:

Antigen presenting cell

BCP:

Breast cancer patient

Cpm:

Counts per minute

CTL:

Cytotoxic T-Lymphocytes

DC:

Dendritic cell

DMSO:

Dimethylsulfoxid

EBV:

Ebstein/barr virus

F:

Female

FCS:

Fetal calf serum

HCMV:

Human cytomegaly virus

HD:

Healthy donor

HLA:

Human leucocyte antigen

IFN:

Interferon

IL:

Interleukin

M:

Male

MUC-1:

Mucin-1

n.t.:

Not tested

PBL:

Peripheral blood lymphocytes

PBMC:

Peripheral blood mononuclear cells

qRT-PCR:

Quantitative real time polymerase chain reaction

TAA:

Tumor associated antigen

TxNxMx:

Clinical classification concerning tumor-, nodal-, and metastases-status

VNTR:

Variable number of tandem repeat

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Acknowledgments

We thank Cécile Gouttefangeas for support, input and helpful discussions. We further acknowledge the expert technical assistance of Beatrice Hoffmann. Our thanks to all the patients and healthy volunteers who agreed to participate in this study. Supported by Grants from the Angewandte Klinische Forschung (AKF)-Programm of the University of Tübingen (Grant 64-0-0) and from the Deutsche Forschungsgemeinschaft (Grant GU 511/2-1).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Tübingen, Calwerstraße 7, 72076, Tübingen, Germany

    Brigitte Gückel, Christine Rentzsch, Alexander Marmé, Ines Gruber, Simone Kayser & Diethelm Wallwiener

  2. Department of Immunology, Institute for Cell Biology, University of Tübingen, 72076 , Tübingen, Germany

    Maria-Dorothea Nastke & Stefan Stevanović

Authors
  1. Brigitte Gückel
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  2. Christine Rentzsch
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  3. Maria-Dorothea Nastke
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  4. Alexander Marmé
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  5. Ines Gruber
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  6. Stefan Stevanović
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  7. Simone Kayser
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  8. Diethelm Wallwiener
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Corresponding author

Correspondence to Brigitte Gückel.

Additional information

Brigitte Gückel and Christine Rentzsch contributed equally to this study.

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Gückel, B., Rentzsch, C., Nastke, MD. et al. Pre-existing T-cell immunity against mucin-1 in breast cancer patients and healthy volunteers. J Cancer Res Clin Oncol 132, 265–274 (2006). https://doi.org/10.1007/s00432-005-0064-6

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  • DOI: https://doi.org/10.1007/s00432-005-0064-6

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