Rapid alphabeta TCR-mediated responses in gammadelta T cells transduced with cancer-specific TCR genes.
Adoptive T-cell transfer of in vitro cultured T cells derived from cancer patients with naturally developed immune responses has met with some success as an immunotherapeutic approach, although only a limited number of patients showed spontaneous immune responses. To find alternative ways, such as cancer-specific T-cell receptor (TCR) gene transfer, in preparation for sufficient numbers of antigen-specific T cells is an important issue in the field of adoptive T-cell therapy. Given the inherent disadvantage of alphabeta TCR transfer to other alphabeta T cells, namely the possible formation of mixed TCR heterodimers with endogenous alpha or beta TCR, we employed gammadelta T cells as a target for retroviral transfer of cancer-specific TCR and examined whether gammadelta T cells were useful as an alternative population for TCR transfer. Although retroviral transduction to gammadelta T cells with TCR alphabeta genes alone, isolated from a MAGE-A4(143-151)-specific alphabeta CD8(+) cytotoxic T lymphocyte (CTL) clone, did not provide sufficient affinity to recognize major histocompatibility (MHC)-peptide complexes due to the lack of CD8 co-receptor, gammadelta T cells co-transduced with TCR alphabeta and CD8 alphabeta genes acquired cytotoxicity against tumor cells and produced cytokines in both alphabeta- and gammadelta-TCR-dependent manners. Furthermore, alphabeta TCR and CD8-transduced gammadelta T cells, stimulated either through alphabeta TCR or gammadelta TCR, rapidly responded to target cells compared with conventional alphabeta T cells, reminiscent of gammadelta T cells. We propose alphabeta TCR-transduced gammadelta T cells as an alternative strategy for adoptive T-cell transfer.
Hiasa
A
A
Department of Immunno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
Nishikawa
H
H
Hirayama
M
M
Kitano
S
S
Okamoto
S
S
Chono
H
H
Yu
S S
SS
Mineno
J
J
Tanaka
Y
Y
Minato
N
N
Kato
I
I
Shiku
H
H
D019264:Adoptive Transfer / Q000379:methods; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D052138:Genes, Neoplasm; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D012190:Retroviridae / Q000235:genetics; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D014407:Tumor Cells, Cultured
D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta