Identification of HLA-A2-restricted epitopes of the tumor-associated antigen MUC2 recognized by human cytotoxic T cells

Abstract

Previous studies have shown that self‐antigens overexpressed in malignant tissue can provide a basis for a tumor‐specific immune response. The mucin MUC2 is strongly overexpressed in all mucinous tumors of colon, breast, ovary and pancreas. In the corresponding normal tissue it is either not expressed (breast, ovary, pancreas) or it is expressed at considerably lower levels than in the mucinous tumors (colon). We therefore investigated whether the MUC2 molecule comprises HLA‐A2‐binding epitopes recognized by human cytotoxic T cells. Four MUC2 peptides with high affinity and stable binding to HLA‐A2 were identified. Those peptides and additionally 3 peptides with moderate binding to HLA‐A2 were loaded onto dendritic cells, which were used for stimulation of autologous T cells from healthy donors. Two MUC2 peptides, which belonged to the group of stable binders, induced specific cytotoxic T‐cell lines. Target cells loaded with these peptides were strongly lysed in a concentration‐dependent and HLA‐A2‐restricted manner. Our data show that the tumor‐associated mucin MUC2 has potential as a target antigen for cytotoxic T cells in patients with mucinous carcinomas. Int. J. Cancer 75:688–693, 1998.© 1998 Wiley‐Liss, Inc.

Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia

“…For the relationship between MUC1 expression and poor prognosis, the following reasons have been considered: that MUC1 mucin functions as (i) an anti‐adhesion molecule which inhibits cell–cell adhesion, inducing the release of cells from the tumor; 27,28 (ii) an inhibitor of the interaction between cytotoxic lymphocytes and tumor cells; 29 (iii) an inhibitor of integrin‐mediated cell adhesion to extracellular matrix; 30 and (iv) a suppressor of the human T‐cell proliferative response inducing immunosuppression 31 . In contrast, for the relationship between MUC2 expression and favorable prognosis, the following reasons seem to be possible: (i) MUC2 mucin has cysteine‐rich domains which may play a role in regulating cell proliferation; 32 and (ii) MUC2 is a potential target antigen for cytotoxic T cells 33 . These explanations may be related to the invasive growth of malignant epithelial tumors.…”

Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and in Crohn's disease increases detectability of the MUC2 protein core

“…33 These antibodies have been shown to react with a high molecular weight protein with a M r >200 kD; 34 whether this antigen is a precursor of mature MUC2 is not known at present. Furthermore, the recent identification of MUC2-derived peptides capable of inducing cytotoxic T cells 35 suggests a cellular response to the nonglycosylated protein part of the MUC2 protein is also conceivable. Further study is necessary to clarify whether the defective post-translational modification of the MUC2 molecule can induce an autoimmune response during UC.…”

Identification of a new HLA-A*0201-restricted T-cell epitope from the tyrosinase-related protein 2 (TRP2) melanoma antigen

“…The binding affinity of each TRP2 peptide and control peptide (tyrosinase 368 -376 ) to HLA-A*0201 was determined as described by Böhm et al (1998). Briefly, T2 cells were incubated overnight with peptide (25 g/ml) in serum-free medium containing human ␤2-microglobulin (␤2-M; 3 g/ml; Sigma, Deisenhofen, Germany).…”