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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2100-2106
IMMUNOBIOLOGY
ALK as a novel lymphoma-associated tumor antigen: identification
of 2 HLA-A2.1-restricted CD8+ T-cell epitopes
Lorena Passoni,
Antonio Scardino,
Carla Bertazzoli,
Barbara Gallo,
Addolorata M. L. Coluccia,
François A. Lemonnier,
Konstadinos Kosmatopoulos, and
Carlo Gambacorti-Passerini
From the Oncogenic Fusion Genes and Proteins Unit,
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
INSERM U.487, Institut Gustave Roussy, Villejuif, France; and
Unité d'Immunité Cellulaire Antivirale, Department
SIDA-Retrovirus, Institut Pasteur, Paris, France.
Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (NPM/ALK
and associated variants) are expressed in about 60% of anaplastic
large cell lymphomas (ALCLs) but are absent in normal tissues. In this
study, we investigated whether ALK, which is expressed at high
levels in lymphoma cells, could be a target for antigen-specific
cell-mediated immunotherapy. A panel of ALK-derived peptides was tested
for their binding affinity to HLA-A*0201 molecules. Binding peptides
were assessed for their capacity to elicit a specific immune response
mediated by cytotoxic T lymphocytes (CTLs) both in vivo, in HLA-A*0201
transgenic mice, and in vitro in the peripheral blood lymphocytes
(PBLs) from healthy donors. Two HLA-A*0201-restricted CTL epitopes,
p280-89 (SLAMLDLLHV) and p375-86 (GVLLWEIFSL), both located in the ALK
kinase domain were identified. The p280-89- and
p375-86-induced peptide-specific CTL lines were able to specifically release interferon- (IFN-) on stimulation with ALK peptide-pulsed autologous Epstein-Barr virus-transformed B cells (LCLs) or T2 cells.
Anti-ALK CTLs lysed HLA-matched ALCL and neuroblastoma cell lines
endogenously expressing ALK proteins. CTL activity was inhibited by
anti-HLA-A2 monoclonal antibody CR11.351, consistent with a class
I-restricted mechanism of cytotoxicity. These results show the
existence of functional anti-ALK CTL precursors within the peripheral
T-cell repertoire of healthy donors, clearly indicating ALK as a tumor
antigen and ALK-derived peptides, p280-89 and p375-86, as suitable
epitopes for the development of vaccination strategies.
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