Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood gammadelta T cells.
BACKGROUND
Vgamma9Vdelta2 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, Vgamma9Vdelta2 T-cell based lymphoma clinical trials have suffered from the lack of biomarkers that can be used as prognostic of therapeutic success.


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 Vgamma9Vdelta2 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 Vgamma9Vdelta2 T cell mediated cytolysis in vitro.


RESULTS
We identified a panel of 10 genes encoding cell surface proteins that were statistically differentially expressed between "gammadelta-susceptible" and "gammadelta-resistant" hematopoietic tumors. Within this panel, 3 genes (ULBP1, TFR2 and IFITM1) were associated with increased susceptibility to Vgamma9Vdelta2 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 Vgamma9Vdelta2 cell-mediated immunotargeting. The prognostic value of the proposed markers can now be evaluated in upcoming Vgamma9Vdelta2 T cell-based lymphoma/leukemia clinical trials.
Gomes
Anita Q
AQ
Unidade de Imunologia Molecular, Instituto de Medicina da Universidade de Lisboa, Moniz, 1649-028 Lisboa, Portugal.
Correia
Daniel V
DV
Grosso
Ana R
AR
Lança
Telma
T
Ferreira
Cristina
C
Lacerda
João F
JF
Barata
João T
JT
Silva
Maria Gomes da
MG
Silva-Santos
Bruno
B
D000943:Antigens, Differentiation / Q000235:genetics; D000954:Antigens, Surface / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019169:Jurkat Cells; D007938:Leukemia / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D000943:Antigens, Differentiation; D000954:Antigens, Surface; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; C423231:ULBP1 protein, human; C062010:leu-13 antigen