Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1)

Karl G. Kohlgraf, Andrew J. Gawron, Michiyo Higashi, Michelle L. VanLith, XiaoLing Shen, Thomas C. Caffrey, Judy M. Anderson, Michael A Hollingsworth

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 (B 16 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.

Original languageEnglish (US)
Pages (from-to)1068-1084
Number of pages17
JournalCancer Immunology, Immunotherapy
Volume53
Issue number12
DOIs
StatePublished - Dec 1 2004

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Subunit Vaccines
Tail
Immunity
Immunization
Tandem Repeat Sequences
Epitopes
Neoplasms
T-Lymphocytes
Transgenic Mice
Peptides
Membrane Glycoproteins
Tumor Cell Line
Autoimmunity
Gastrointestinal Tract
Pancreas
Amino Acid Sequence
Breast
Epithelium
Complementary DNA
Lung

Keywords

  • Antitumor immunotherapy
  • In vivo epitope mapping
  • MUC1
  • Tumor immunity
  • Tumor-associated antigens

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1). / Kohlgraf, Karl G.; Gawron, Andrew J.; Higashi, Michiyo; VanLith, Michelle L.; Shen, XiaoLing; Caffrey, Thomas C.; Anderson, Judy M.; Hollingsworth, Michael A.

In: Cancer Immunology, Immunotherapy, Vol. 53, No. 12, 01.12.2004, p. 1068-1084.

Research output: Contribution to journalArticle

Kohlgraf, Karl G. ; Gawron, Andrew J. ; Higashi, Michiyo ; VanLith, Michelle L. ; Shen, XiaoLing ; Caffrey, Thomas C. ; Anderson, Judy M. ; Hollingsworth, Michael A. / Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1). In: Cancer Immunology, Immunotherapy. 2004 ; Vol. 53, No. 12. pp. 1068-1084.
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T1 - Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1)

AU - Kohlgraf, Karl G.

AU - Gawron, Andrew J.

AU - Higashi, Michiyo

AU - VanLith, Michelle L.

AU - Shen, XiaoLing

AU - Caffrey, Thomas C.

AU - Anderson, Judy M.

AU - Hollingsworth, Michael A

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AB - 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 (B 16 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.

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KW - MUC1

KW - Tumor immunity

KW - Tumor-associated antigens

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