Identification of an immunogenic CD8+ T-cell epitope derived from gamma-globin, a putative tumor-associated antigen for juvenile myelomonocytic leukemia.
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. Gamma-globin, an oncofetal protein overexpressed by clonogenic JMML cells, may serve as a target of an antitumor immune response. We predicted 5 gamma-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 gamma-globin(+), but not gamma-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 gamma-globin-derived epitope g105.
Hirano
Naoto
N
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA. naoto_hirano@dfci.harvard.edu
Butler
Marcus O
MO
Xia
Zhinan
Z
Berezovskaya
Alla
A
Murray
Andrew P
AP
Ansén
Sascha
S
Kojima
Seiji
S
Nadler
Lee M
LM
D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000302:isolation & purification*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D000939:Epitopes / Q000302:isolation & purification; D005914:Globins / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D000939:Epitopes; D015789:HLA-A2 Antigen; D005914:Globins