MUC1-Specific Cytotoxic T Lymphocytes in Cancer Therapy: Induction and Challenge

Abstract

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.

Phase I/II study exploring ImMucin, a pan‐major histocompatibility complex, anti‐MUC1 signal peptide vaccine, in multiple myeloma patients

“…We can ascribe this strong and broad immune response to the lipophilic sequences within SP domains, such as MUC1‐SP‐L, which has been shown by us (Kovjazin et al , ,b, ; Kovjazin & Carmon, ) and others (Wilkinson et al , ; Kerzerho et al , ) to be more immunogenic than other protein domains, and which, in the case of ImMucin, can generate a rapid response, using a low dose of naked LP administered in conjunction with hGM‐CSF, without employing a dedicated ‘carrier system’ or specific adjuvants. In contrast, other anti‐MUC1 vaccination strategies primarily induce humoral responses and/or selected CD8+ T‐cell activation in a subset of patients (Roulois et al , ). In addition, MUC1‐SP‐L, as a LP, harbours many overlapping epitopes, with predicted binding to a wide range of MHC class I and II alleles, which is thought to enable broader and stronger activation of MUC1 SP specific CD4+ and CD8+ T‐cell clones.…”

Adaptive immune activation: glycosylation does matter

“…In this respect, the mucin MUC1 is often aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides such as Tn (αGalNAc-Thr), STn (αNeu5Ac-(2,6)-αGalNAc-Thr) and Thomsen-Friedenreich antigen (βGal-(1,3)-αGalNAc-Thr) 69 . CTLs isolated from patients with breast carcinoma can recognize epitopes derived from the MUC1 tandem repeat peptide 70 . It has been proposed that tumor cells present epitopes derived from the core domain of MUC1 in their truncated glycosylation state in complex with MHC-I molecules, leading to natural MHC-restricted recognition of ‘hypoglycosylated’ epitopes 59,71-73 .…”

IgE Immunotherapy Against Cancer

“…MUC1 (Mucin 1, cell surface associated) is expressed at the apical surface of healthy epithelial cells and is characterized by a high glycosylation level (Roulois et al 2013). It is overexpressed on tumors arising from glandular epithelium, such as the breast, ovary, pancreas, and colon cancers (Gourevitch et al 1995; Kotera et al 1994), with a loss of polarity and modification of its glycosylation pattern (Roulois et al 2013).…”

“…It is overexpressed on tumors arising from glandular epithelium, such as the breast, ovary, pancreas, and colon cancers (Gourevitch et al 1995; Kotera et al 1994), with a loss of polarity and modification of its glycosylation pattern (Roulois et al 2013). A mouse/human chimeric IgE specific for the human MUC1 antigen has been developed (Teo et al 2012).…”