In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas.
OBJECTIVE
Anaplastic lymphoma kinase (ALK) oncogenic fusion proteins, expressed in about 60% of anaplastic large cell lymphomas (ALCL), are tumor-specific molecular targets for such a malignancy. One of the promising ALK-targeted therapeutic options is cancer vaccination. In this study, we investigate whether ALK is a tumor-associated antigen suitable for immune interventions.


METHODS
The frequency and the functional phenotype of the anti-ALK CD8 precursor repertoire in freshly isolated peripheral blood mononuclear cells (PBMC) from healthy donors and ALK-positive patients were determined by major histocompatibility complex (MHC)/tetrameric analyses. The anti-ALK secondary immune responses were evaluated as PBMC-specific interferon (INF-gamma) release by ELISPOT. In addition, the ability of the anti-ALK immune response to specifically lyse ALK-positive lymphoma cells was investigated by in vitro stimulation with ALK-derived peptide p280-89.


RESULTS
Tetrameric MHC/peptide complexes revealed high frequencies of CD8/ALK-tetramer-positive cells both in patients and in healthy individuals. However, the functional phenotype of the CD8/ALK-tetramer-positive lymphocytes showed the presence of effector and memory T lymphocytes only in patients. The anti-ALK cytotoxic T lymphocytes (CTL) of patients, but not healthy donors, displayed thresholds of activation comparable to those of CTL precursors of a recall antigen (influenza virus). A polyclonal ALK-specific tumor-reactive T-cell line was isolated from patients' peripheral blood lymphocytes.


CONCLUSIONS
The presence of an anti-ALK effector/memory lymphocyte population in the peripheral blood of ALK-positive patients indicates an in vivo antigenic challenge. Thus, ALK is a lymphoma-associated antigen suitable for immune interventions. The high number of anti-ALK memory CD8 T cells present in patients' PBMC may represent a valid source of activated CTL suitable for cancer cell lysis.
Passoni
Lorena
L
Oncogenic Fusion Protein Unit, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. lorena.passoni@istitutotumori.mi.it
Gallo
Barbara
B
Biganzoli
Elia
E
Stefanoni
Roberta
R
Massimino
Maura
M
Di Nicola
Massimo
M
Gianni
Alessandro M
AM
Gambacorti-Passerini
Carlo
C
D000077548:Anaplastic Lymphoma Kinase; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D016022:Case-Control Studies; D003602:Cytotoxicity, Immunologic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases