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Advisor(s)
Abstract(s)
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.
Description
Keywords
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
Citation
Gomes AQ, Correia DV, Grosso AR, Lança T, Ferreira C, Lacerda JF, et al. dentification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood γδ T cells. Haematologica. 2010;95(8):1397-404.
Publisher
Ferrata Storti Foundation