MUC1 Immunobiology: From Discovery to Clinical Applications
Introduction
For more than a decade, tumor immunologists have focused their efforts on discovering tumor-associated antigens, as a first step toward the design of an effective cancer vaccine. To date, approximately 70 MHC class I and II-associated tumor antigens have been described, while more than 1700 have been identified by antibodies in cancer patients (Yu and Restifo, 2002). However, it has become increasingly evident that this growing list of putative tumor-associated antigens will need to be supplemented with greater understanding of their molecular nature and mechanisms of action in order to validate them as suitable targets for tumor immunotherapy.
In this chapter we will highlight studies on MUC1, one of the first tumor antigens shown to be a target for human tumor-specific T cells and thus a valid target for immunotherapy. MUC1 is a member of the mucin family of molecules. It is expressed on the luminal surface of most polarized epithelial cells and overexpressed over the entire cell surface of most adenocarcinomas. Cancer-associated MUC1 is different from MUC1 on normal cells. During tumor progression there are changes in glycosylation that result in the synthesis of tumor-specific glycoforms bearing novel T and B cell epitopes. Thus MUC1 glycoprotein meets the criteria of a tumor-specific antigen and is currently employed in vaccines under investigation in several clinical trials.
Research on MUC1 has been reported in over 700 publications in the past 5 years, with the majority of these publications being focused on MUC1 immunobiology. These numbers, illustrating the interest in this molecule as an important tool in cancer research, also indicate the amplitude of the ongoing efforts to further explore the basic mechanisms behind its immunogenicity and its suitability as a target antigen for cancer treatment and prevention. We will briefly describe here the key research efforts that elucidate MUC1 structure and biosynthesis pathways; however, our emphasis will be on the most recent studies that mark progress toward a better understanding of what makes MUC1 a tumor antigen, what kind of immune responses this molecule can trigger, and how various immune effector mechanisms can be manipulated for therapeutic purposes.
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History of MUC1, the Pioneer Member of the Mucin Family
MUC1 was first identified in the milk fat globule membrane fraction and described as a protein rich in serine, threonine, proline, glycine, and alanine (Shimizu and Yamauchi, 1982). It was found to contain a high percentage of O-linked carbohydrates that accounted for about 50% of its molecular weight. In 1987, Gendler and colleagues (1987) were able to clone a fragment from this first human mucin gene by screening a mammary tumor cell line MCF-7 cDNA library using antibodies raised against a
MUC1 Structure and Biosynthesis
Unlike the majority of mucins that are secreted from cells, MUC1 is expressed as both a transmembrane and secreted form. Though it is encoded as a single protein, it is expressed as a type I transmembrane heterodimer. The two proteins that make up MUC1 differ greatly in size, with most of the larger MUC1 fragment being composed of a tandemly repeated 20 amino acid sequence, PDTRPAPGSTAPPAHGVTSA. This serine-, threonine-, and proline-rich sequence can be repeated up to 125 times in a single MUC1
In Healthy Humans
The presence of anti-MUC1 antibodies of IgM and IgG isotypes, as well as of circulating MUC1 antigen in sera from normal healthy women, is well documented (Richards et al., 1998). Agrawal et al. (1995) have shown that MUC1-specific T cells can be primed during pregnancy, as T cells from biparous but not nulliparous women proliferated specifically in response to core MUC1 peptides. These findings could be explained by the fact that anatomical and physiological changes of MUC1-expressing organs
Peptide Vaccines
Vaccines based on synthetic peptides have the advantage of being readily available, although they require the identification of exact epitopes recognized by T or B cells. Most peptide vaccines have been tested for their ability to elicit strong CTL responses; however, optimal vaccine formulations should also include one or more antigen-specific T helper epitopes. Helper responses to MUC1 have not been detected to date in cancer patients. Therefore identification of MUC1-derived helper epitopes
MUC1 Vaccines in Clinical Trials
Vaccines based on MUC1 are currently tested in cancer patients with advanced tumors for therapeutic purposes. In recent years, advances in basic immunology and biotechnology have contributed to the design of vaccines with better immunogenic properties. Development of MUC1 antigens with increased immunogenicity, discovery of more potent adjuvants, and design of efficient antigen delivery systems are all important contributions for clinical applications of MUC1 vaccines. Some of these
Conclusions and Future Perspectives
Important developments in MUC1 research have provided new insights to our understanding of how MUC1 glycoprotein changes during premalignant and later malignant transformation and how these changes are recognized by various immune effector mechanisms. It has been demonstrated by us and others that MUC1 is antigenic: cancer patients with MUC1-positive tumors generate anti-MUC1 antibodies and MUC1-specific CTLs. However, in a tumor environment, these immune responses are inefficient at
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