Author(s):
Gomes, Anita Q. ; Correia, Daniel V. ; Grosso, Ana R. ; Lanca, Telma ; Ferreira, Cristina ; Lacerda, João F. ; Barata, João T. ; Silva, Maria Gomes da ; Silva-Santos, Bruno
Date: 2010
Persistent ID: http://hdl.handle.net/10400.21/12196
Origin: Repositório Científico do Instituto Politécnico de Lisboa
Subject(s): Antigens, Differentiation; Antigens, Surface; Cell line, Tumor; Cells, Cultured; Cytotoxicity, Immunologic; GPI-linked proteins; Genetic predisposition to disease; Humans; Intracellular signaling peptides and proteins; Jurkat cells; Leukemia; Leukocytes, Mononuclear; Lymphoma; Membrane Proteins; Oligonucleotide array sequence analysis; Prognosis; Receptors, Antigen; Receptors, Transferrin; Reverse transcriptase polymerase chain reaction; T-Lymphocytes; Gene expression profiling; T-Cell; Gamma-delta
Description
Background: Vγ9Vδ2 T lymphocytes are regarded as promising mediators of cancer immunotherapy due to their capacity to eliminate multiple experimental tumors, particularly within those of hematopoietic origin. However, Vγ9Vδ2 T-cell based lymphoma clinical trials have suffered from the lack of biomarkers that can be used as prognostic of therapeutic success. Design and Methods: We have conducted a comprehensive study of gene expression in acute lymphoblastic leukemia and non-Hodgkin’s lymphomas, aimed at identifying markers of susceptibility versus resistance to Vγ9Vδ2 T cell-mediated cytotoxicity. We employed cDNA microarrays and quantitative real-time PCR to screen 20 leukemia and lymphoma cell lines, and 23 primary hematopoietic tumor samples. These data were analyzed using state-of-the-art bioinformatics, and gene expression patterns were correlated with susceptibility to Vγ9Vδ2 T cell-mediated cytolysis in vitro. Results: We identified a panel of 10 genes encoding cell surface proteins that were statistically differentially expressed between “γδ-susceptible” and “γδ-resistant” hematopoietic tumors. Within this panel, 3 genes (ULBP1, TFR2, and IFITM1) were associated with increased susceptibility to Vγ9Vδ2 T-cell cytotoxicity, whereas the other 7 (CLEC2D, NRP2, SELL, PKD2, KCNK12, ITGA6, and SLAMF1) were enriched in resistant tumors. Furthermore, some of these candidates displayed a striking variance of expression among primary follicular lymphomas and T-cell acute lymphoblastic leukemias. Conclusions: Our results suggest that hematopoietic tumors display a highly variable repertoire of surface proteins that can impact on Vγ9Vδ2 cell-mediated immune targeting. The prognostic value of the proposed markers can now be evaluated in the upcoming Vγ9Vδ2 T cell-based lymphoma/leukemia clinical trials.
