In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas
Passoni, L.; Gallo, B.; Biganzoli, E.; Stefanoni, R.; Massimino, M.; Di Nicola, M.; Gianni, A.M.; Gambacorti-Passerini, C.
Haematologica 91(1): 48-55
2006
ISSN/ISBN: 0390-6078 PMID: 16434370 Document Number: 596864
Background and Objectives, 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.Design and 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 ant.i-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 riot 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.Interpretation and 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.