MUC1 (12-20) peptide (LLLLTVLTV) – Type 1 Mucin Tumor-Associated Antigen
MUC1 (Mucin 1) protein is a type 1 transmembrane glycoprotein characterized by a large extracellular domain containing a variable number (up to 120) of 20-amino acid repeat sequences (PDTRPAPGSTAPPAHGVTSA) and a high glycosylation level on serine and threonine residues within each tandem repeat1. MUC1 protein is expressed at the apical part of secretory epithelial cells and is involved in the protection of epithelial surfaces as well as intracellular signalling.
However, the aberrant MUC1 overexpression along with the modification of its glycosylation pattern has been associated with several carcinomas including more than 90% of breast and pancreas cancers as wells as hematologic malignancies such as multiple myelomas and lymphomas2. These hallmarks make MUC1 highly immunogenic when its expressed in tumor cells and, thus, an attractive and broadly applicable target for cancer inmunotherapy.
MUC1 has indeed prompted research to develop T-cell vaccine strategies capable of inducing MUC1-specific cytotoxic T lymphocyte responses in cancer patients upon immunization with a MUC1 antigenic epitope. MUC1 epitopes presented by the HLA-A*0201 molecules are most studied and the capacity of MHC-restricted cytotoxic T lymphocytes (CTLs) to recognize MUC1-expressing tumor cells is assessed to validate the epitope1.
The HLA-A2-restricted MUC1 (12-20) peptide (LLLLTVLTV) derives from the leader sequence of MUC1 protein and has demonstrated the ability to induce MUC1-specific CTL responses3. Nevertheless, the immunodominant region of the tandem repeat domain (amino acids 950– 958, STAPPVHNV) has been also recognized by MUC1-specific CTLs in an antigen-specific and HLA-A2-restricted fashion3.
The half maximal inhibitory concentrations (IC50) for the MUC1 (950– 958) peptide and the MUC1 (12-20) peptide have been determined using a competitive peptide inhibition assay and were 10.13 µg/ml and 10.89 µg/ml, respectively2. Hence, these two peptides fall within the IC50 range for “medium binders”. Recently, It hase been reported that optimization of MUC1 (950– 958) peptides through specific amino acid substitution and/or aberrant glycosylation showed higher binding affinities, with IC50 ranging from 0.34 to 1.68 µg/ml. Thus, modified peptides can be considered as « high-affinity binders » which may serve for developing more efficient MUC1-specfic cancer vaccines2.
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1-Roulois, D., Grégoire, M. & Fonteneau, J.-F. BioMed Research International (2013)
MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.
2-Pathangey, L. B. et al. Biomolecules 6, 31 (2016)
Aberrant Glycosylation of Anchor-Optimized MUC1 Peptides Can Enhance Antigen Binding Affinity and Reverse Tolerance to Cytotoxic T Lymphocytes
Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines.
3-Brossart, P. et al. Cancer Res. 61, 6846–6850 (2001)
The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes
The epithelial mucin MUC1 is overexpressed on the cell surface of many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. Recently, we identified two HLA-A2-restricted T-cell epitopes derived from the MUC1 protein. To further extend the potential application of these peptides, we analyzed the expression of MUC1 on blast cells from patients with acute myelogenous leukemia (AML; n = 43) and several other hematological malignancies including acute lymphoblastic leukemia (n = 24), chronic lymphocytic leukemia (n = 36), hairy cell leukemia (n = 9), follicular lymphoma (n = 7), and multiple myeloma (n = 12). Using reverse transcription-PCR and MUC1-specific monoclonal antibodies, MUC1 expression was found in 67% of AML samples and 92% of myeloma samples. To analyze the presentation of MUC1 peptides by primary AML blasts, we induced MUC1-specific CTLs in vitro using peptide-pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed in an antigen-specific and HLA-A2-restricted manner not only target cells pulsed with the antigenic peptide but also tumor cell lines including multiple myeloma cells and primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML and several other hematological malignancies that could potentially be used for immunotherapeutic approaches.
4-Coulie, P. G., Eynde, B. J. V. den, Bruggen, P. van der & Boon, T. Nat. Rev. Cancer 14, 135 (2014)
In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.