Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood γδ T cells

Background V gamma 9V delta 2 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, V gamma 9V delta 2 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 leukemias and non-Hodgkin's lymphomas, aimed at identifying markers of susceptibility versus resistance to V gamma 9V delta 2 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 V gamma 9V delta 2 T-cell-mediated cytolysis in vitro. Results We identified a panel of 10 genes encoding cell surface proteins that were statistically differentially expressed between "gamma delta-susceptible" and "gamma delta-resistant" hematopoietic tumors. Within this panel, 3 genes (ULBP1, TFR2 and IFITM1) were associated with increased susceptibility to V gamma 9V delta 2 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 V gamma 9V delta 2 cell-mediated immunotargeting. The prognostic value of the proposed markers can now be evaluated in upcoming V gamma 9V delta 2 T cell-based lymphoma/leukemia clinical trials.