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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4309-4317
Identification of HLA-A2-Restricted T-Cell Epitopes Derived From the
MUC1 Tumor Antigen for Broadly Applicable Vaccine Therapies
Peter Brossart,
Kathrin S. Heinrich,
Gernot Stuhler,
Lars Behnke,
Volker L. Reichardt,
Stefan Stevanovic,
Alexandra Muhm,
Hans-Georg Rammensee,
Lothar Kanz, and
Wolfram Brugger
From the Department of Hematology, Oncology and Immunology,
University of Tübingen, Tübingen, Germany; and the
Department of Immunology, Institute for Cell Biology, Tübingen,
Germany.
The tumor-associated antigen MUC1 is overexpressed on various
hematological and epithelial malignancies and is therefore a suitable
candidate for broadly applicable vaccine therapies. It was demonstrated
that major histocompatibility complex (MHC)-unrestricted cytotoxic T cells can recognize epitopes of the MUC1 protein core localized in the tandem repeat domain. There is increasing evidence now
that MHC-restricted T cells can also be induced after immunization with
the MUC1 protein or segments of the core tandem repeat. Using a
computer analysis of the MUC1 amino acid sequence, we identified two
novel peptides with a high binding probability to the HLA-A2 molecule.
One of the peptides is derived from the tandem repeat region and the
other is derived from the leader sequence of the MUC1 protein,
suggesting that, in contrast to previous reports, the MUC1-directed
immune responses are not limited to the extracellular tandem repeat
domain. Cytotoxic T cells (CTL) were generated from several healthy donors by primary in vitro immunization using peptide-pulsed dendritic cells. The addition of a Pan-HLA-DR binding peptide PADRE as a T-helper epitope during the in vitro priming resulted in an increased cytotoxic activity of the MUC1-specific CTL
and a higher production of cytokines such as interleukin-12 and
interferon- in the cell cultures, demonstrating the importance of
CD4 cells for an efficient CTL priming. The peptide induced CTL lysed
tumors endogenously expressing MUC1 in an antigen-specific and
HLA-A2-restricted fashion, including breast and pancreatic tumor cells
as well as renal cell carcinoma cells, showing that these peptides are
shared among many tumors. The use of MUC1-derived peptides could
provide a broadly applicable approach for the development of dendritic
cell-based vaccination therapies.
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