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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2662-2668.
Prepublished online as a Blood First Edition Paper on June 15, 2006; DOI 10.1182/blood-2006-04-017566.
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IMMUNOBIOLOGY
Identification of an immunogenic CD8+ T-cell epitope derived from  -globin, a putative tumor-associated antigen for juvenile myelomonocytic leukemia
Naoto Hirano,
Marcus O. Butler,
Zhinan Xia,
Alla Berezovskaya,
Andrew P. Murray,
Sascha Ansén,
Seiji Kojima, and
Lee M. Nadler
From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital, Boston, MA; the Department of Medicine, Harvard Medical School, Boston, MA; and the Department of Pediatrics, Nagoya University, Japan.
Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder. Although allogeneic stem cell transplantation can induce long-term remissions, relapse rates remain high and innovative approaches are needed. Since donor lymphocyte infusions have clinical activity in JMML, T-cell-mediated immunotherapy could provide a nonredundant treatment approach to compliment current therapies.  -Globin, an oncofetal protein overexpressed by clonogenic JMML cells, may serve as a target of an antitumor immune response. We predicted 5 -globin-derived peptides as potential human leukocyte antigen (HLA)-A2 restricted cytotoxic T lymphocyte (CTL) epitopes and showed that 4 (g031, g071, g105, and g106) bind A2 molecules in vitro. Using an artificial antigen-presenting cell (aAPC) that can process both the N- and C-termini of endogenously expressed proteins, we biochemically confirmed that g105 is naturally processed and presented by cell surface A2. Furthermore, g105-specific CD8+ CTLs generated from A2-positive healthy donors were able to specifically cytolyze -globin+, but not -globin- JMML cells in an A2-restricted manner. These results suggest that this aAPC-based approach enables the biochemical identification of CD8+ T-cell epitopes that are processed and presented by intact cells, and that CTL immunotherapy of JMML could be directed against the -globin-derived epitope g105.
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