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Cancer cell MUC1: At the tumor stem

Functional Glycomics (08 May 2008) | doi:10.1038/fg.2008.22

The transmembrane mucin MUC1 occurs in a stem cell subpopulation of the breast cancer cell line MCF-7, and can be targeted in an immunotherapeutic approach by chimeric antigen T-cell receptors.

Schematic diagram of full-length MUC1. From Brayman, M. et al. MUC1: A multifunctional cell surface component of reproductive tissue epithelia. Reprod Biol Endocrinol 2, 4 (2004). Click here for a full size image. Copyright © 2004 Brayman et al.; licensee BioMed Central Ltd

Concurrent with malignant development, many types of epithelial cell upregulate the expression of MUC1. At the same time, cancer cell MUC1 carries abnormal glycans; for instance, in breast cancer upregulation of the ST3GAL1 sialyltransferase leads to shorter and more sialylated glycans. These features seem to make MUC1 a strong candidate for anti-cancer therapies, particularly for immunotherapeutic approaches. However, a complete eradication of cancer must include cancer stem cells. Thus, is MUC1 also found on breast cancer stem cells, and can antibodies be raised that are specific for the MUC1 glycoepitope and that elicit a cytotoxic T-cell response? Engelmann et al. in Cancer Research and Wilkie et al. in the Journal of Immunology now address these questions.

Screening a panel of epithelial cancer cell lines, Engelmann et al. searched for subgroups of cells with stem-cell characteristics. They found that a cell population from the breast cancer cell line MCF-7 possessed numerous stem-cell markers (hence termed MCF-7 SP). Among these were the drug-resistance protein ABCG2, the epithelial-cell adhesion molecule EpCAM and the cytokeratin CK18. MCF-7 SP also had a CD44+/CD24low profile, which has been shown to be typical for breast cancer stem cells. Importantly, the presence of MUC1 on the MCF-7 SP cells mirrored the expression found on mature MCF-7 cells: in most of the MCF-7 SP cells (MUC1bright cells), MUC1 was dispersed across the cell surface, whereas only a small group lacked a strong MUC1 expression (MUC1dim).

MCF-7 SP MUC1 mostly carried a trisaccharide composed of sialic acid, galactose and N-acetylgalactosamine (also known as sialyl-core 1 or sialyl-T antigen), and shorter glycans such as sialylated N-acetylgalactosamine (sialyl-Tn antigen). When Engelmann et al. injected MUC1bright MCF-7 SP cells into immunocompromised mice, they observed growth of tumors mostly containing MUC1bright cells which retained a subpopulation of stem-cell-like cells. These results indicate that MCF7 breast cancer cells possess a subpopulation of stem cells carrying large amounts of MUC1, which is an important prerequisite for successful MUC1-targeted tumor therapy.

Wilkie et al. describe the development of chimeric antibody T-cell receptors (CARs) against MUC1. When CARs recognize their antigens, T cells are activated, leading to cytotoxic T-cell proliferation and production of interferon-gamma, which eventually destroys the cells carrying the activating antigen. Wilkie et al. found that CAR-bearing cytotoxic T cells destroyed breast cancer cells more efficiently when the CAR Fab (fragment antigen-binding) region – consisting of an anti-MUC1 antibody – was fused to the Fc (fragment crystallizable) region by a flexible linker derived from the immunoglobulin D molecule.

Next, a trimodular CAR was created (termed HOX CAR). This included the OX40 receptor that enhances T-cell proliferation and cytokine production upon T-cell activation, and an Fab region derived from the HMFG2 antibody which reacts strongly against the MUC1 glycoform carrying the sialyl-T-antigen. From all the CAR constructs tested, the HOX variant led to the largest production of IL-2 and interferon-gamma. Indeed, HOX-expressing T cells effectively destroyed a T47D but not a normal epithelial cell monolayer which expresses smaller amounts of other MUC1 glycoforms. HOX-grafted T cells injected into tumor-bearing mice led to a significant delay in tumor growth and increased survival time. Thus, this study is a successful application of the CAR technique against the MUC1 glycoprotein.

Mirko von Elstermann

Original paper:

  1. Engelmann, K., Shen, H. & Finn, O.J.
    MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1.
    Cancer Research 68, 2419–2426 (2008).
    doi:10.1158/0008-5472.CAN-07-2249 | Article |
  2. Wilkie, S. et al.
    Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor.
    Journal of Immunology 180, 4901–4909 (2008).
    | Article |