PURPOSE: CD227 (MUC1), a membrane-associated glycoprotein expressed by many types of ductal epithelia, including pancreas, breast, lung, and gastrointestinal tract, is overexpressed and aberrantly glycosylated by malignant cells. We sought to define epitopes on MUC1 recognized by the different cell-mediated immune responses by an in vivo assay. Epitopes identified by this assay were evaluated for efficacy to protect mice transgenic for human MUC1 (MUC1.Tg) against MUC1-expressing tumor growth. METHODS: We investigated contributions of the tandem repeat (TR) and the cytoplasmic tail (CT) of MUC1 to the MUC1-specific immunological rejection of tumor cells. MUC1 cDNA constructs, in which the TR region was deleted or the CT was truncated, were transfected into two different murine tumor cell lines (B16 and Panc02), which were used to challenge mice and evaluate immunological rejection of the tumors. We used tumor rejection in vivo to define epitopes on the TR and CT of MUC1 recognized by T cell-mediated immune responses in a preclinical murine model. RESULTS: Our findings demonstrated that the TR and a portion of the MUC1 CT contributed to CD4+ T cell rejection of MUC1-expressing B16 tumor cells, but not rejection of MUC1-expressing Panc02 tumor cells. A separate epitope in the CT of MUC1 was necessary for CD8+ T cell rejection of Panc02 tumor cells. Based on these studies, we sought to evaluate the efficacy of immunizing mice transgenic for (and immunologically tolerant to) human MUC1 with peptides derived from the amino acid sequence of the CT of MUC1. Results showed that survival can be significantly prolonged in vaccinated MUC1.Tg mice challenged with MUC1-expressing tumor cells, without induction of autoimmune responses. CONCLUSIONS: These studies demonstrated that MUC1 peptides may be utilized as an effective anticancer immunotherapeutic, and confirmed the importance of immunogenic epitopes outside of the TR.
PURPOSE:CD227 (MUC1), a membrane-associated glycoprotein expressed by many types of ductal epithelia, including pancreas, breast, lung, and gastrointestinal tract, is overexpressed and aberrantly glycosylated by malignant cells. We sought to define epitopes on MUC1 recognized by the different cell-mediated immune responses by an in vivo assay. Epitopes identified by this assay were evaluated for efficacy to protect mice transgenic for humanMUC1 (MUC1.Tg) against MUC1-expressing tumor growth. METHODS: We investigated contributions of the tandem repeat (TR) and the cytoplasmic tail (CT) of MUC1 to the MUC1-specific immunological rejection of tumor cells. MUC1 cDNA constructs, in which the TR region was deleted or the CT was truncated, were transfected into two different murinetumor cell lines (B16 and Panc02), which were used to challenge mice and evaluate immunological rejection of the tumors. We used tumor rejection in vivo to define epitopes on the TR and CT of MUC1 recognized by T cell-mediated immune responses in a preclinical murine model. RESULTS: Our findings demonstrated that the TR and a portion of the MUC1 CT contributed to CD4+ T cell rejection of MUC1-expressing B16 tumor cells, but not rejection of MUC1-expressing Panc02 tumor cells. A separate epitope in the CT of MUC1 was necessary for CD8+ T cell rejection of Panc02 tumor cells. Based on these studies, we sought to evaluate the efficacy of immunizing mice transgenic for (and immunologically tolerant to) humanMUC1 with peptides derived from the amino acid sequence of the CT of MUC1. Results showed that survival can be significantly prolonged in vaccinated MUC1.Tgmice challenged with MUC1-expressing tumor cells, without induction of autoimmune responses. CONCLUSIONS: These studies demonstrated that MUC1 peptides may be utilized as an effective anticancer immunotherapeutic, and confirmed the importance of immunogenic epitopes outside of the TR.
Authors: Kamiya Mehla; Jarrod Tremayne; James A Grunkemeyer; Kelly A O'Connell; Maria M Steele; Thomas C Caffrey; Xinyi Zhu; Fang Yu; Pankaj K Singh; Birgit C Schultes; Ragupathy Madiyalakan; Christopher F Nicodemus; Michael A Hollingsworth Journal: Cancer Immunol Immunother Date: 2017-12-04 Impact factor: 6.968
Authors: Vani Lakshminarayanan; Nitin T Supekar; Jie Wei; Dustin B McCurry; Amylou C Dueck; Heidi E Kosiorek; Priyanka P Trivedi; Judy M Bradley; Cathy S Madsen; Latha B Pathangey; Dominique B Hoelzinger; Margreet A Wolfert; Geert-Jan Boons; Peter A Cohen; Sandra J Gendler Journal: PLoS One Date: 2016-01-20 Impact factor: 3.240