Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells

The present study analyzed the antitumor effect of gamma delta T cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCR alpha beta genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCR alpha beta and CD8 genes were transduced into gamma delta T cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCR alpha beta-CD8 gamma delta T cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-gamma against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCR alpha beta-CD8 transduced gamma delta T cells (TCR alpha beta-CD8 gamma delta T cells) were intravenously injected. Growth inhibition of KK-LC-1(+), HLA-B15(+)lung cancer cells was confirmed in mice with injection of the TCR alpha beta-CD8 gamma delta T cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCR alpha beta-CD8 gamma delta T cells injection. These results suggested that apoptosis of Fas-positive TCR alpha beta-CD8 gamma delta T cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.