Latest developments in MUC1 immunotherapy

Abstract

Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of approval for general application has not as yet been achieved. However, this does not appear to have quelled the interest in MUC1 as a therapeutic target, as shown by the increase in the number of MUC1-based clinical trials initiated in 2017 ( Figure 1). As with all translational studies, incorporating new relevant research findings into therapeutic strategy is difficult. Decisions are made to commit to a specific strategy based on the information and data available when the trial is initiated. However, the time required for preclinical studies and early trials can render the founding concept not always appropriate for proceeding to a larger definitive trial. Here, we summarize the attempts made, to date, to bring MUC1 into the world of cancer immunotherapy and discuss how research findings regarding MUC1 structure and function together with expanded knowledge of its interactions with the tumour environment and immune effector cells could lead to improved therapeutic approaches. ppbiost;46/3/659/BST20170400CF1F1BST-2017-0400CF1Figure 1.Number of MUC1-targeted trials initiated each year.

Keywords: MUC1; cancer; immunotherapy.

Figure 1.. Number of MUC1-targeted trials initiated each year.

Figure 2.. The structure of the MUC1 mucin.

During translation, MUC1 is cleaved into two domains, MUC1-N and MUC1-C. MUC1-N consists predominantly of the TR domain and the sequence of a single repeat is illustrated. The TR domain is glycosylated with O-linked glycans (in red) and each repeat has five potential sites shown in bold. There are also sites for O-linked glycosylation in the degenerate TRs located to the N- and C-termini of the repeats. There are five potential sites for N-linked glycosylation close to the membrane (in black). MUC1-C consists of 58 amino acids of the external domain, the transmembrane domain (in blue, 28 aa) and the cytoplasmic domain (MUC1-CD, 72 aa). Within the CD1 domain, the CQC trimer is responsible for homodimerization. There are many phosphorylation sites within the CD domain and two of these are indicated. The CQC containing peptide (GO-232) targets the homodimerization domain.

Figure 3.. Simplified pathways of mucin-type O-linked glycosylation in normal and malignant breast epithelial cells.

The Tn glycan can be carried on MUC1 expressed by a high proportion of breast cancers. The STn glycan is found in ∼25% of breast cancers, while ST is more commonly expressed. The unsialylated core 1 (T) is also widely found on MUC1 expressed by breast cancers. In contrast, the glycans found on MUC1 expressed by normal mammary epithelial cells are core 2 based.

Figure 4.. Current and potential clinical approaches targeting MUC1 in cancer.

Current strategies fall into six broad categories (as shown in the boxes) ranging from preclinical to Phase III. The bullet point within each box gives an example of that category of immunotherapy. To date, no therapeutic targeting MUC1 has been approved for general use. GM, genetically modified; DC, dendritic cell; APC, antigen-presenting cell; NK, natural killer.