Lack and restoration of sensitivity of lung cancer cells to cellular attack with special reference to expression of human leukocyte antigen class I and/or major histocompatibility complex class I chain related molecules A/B

Abstract

Both cytotoxic T lymphocytes (CTL) and natural killer (NK) cells may play major roles in the host defense against cancer. However, their relationship against the same tumor remains to be elucidated. Among 26 human lung cancer cell lines established in our laboratory, 10 (38%) exhibited human leukocyte antigen (HLA)-class I haplotype loss and three (12%) lost HLA-class I expression totally by flow cytometry analysis. The two cell lines (E522L and C831L) that lost their expression of HLA-class I in vitro and in vivo were applied for further evaluations. Genetic abnormalities of beta2-microglobulin gene were observed in both E522L (loss of mRNA) and C831L (point mutation). Transduction of the wild-type beta2-microglobulin gene rendered them positive for HLA-class I expression. The CTL were induced from autologous peripheral blood mononuclear cells or regional lymph node lymphocytes by stimulation with wild-type beta2-microglobulin transduced-E522L or -C831L, and they showed tumor-specific cytotoxicity against wild-type beta2-microglobulin-transductant, but not parental cells. In NK cell cytotoxicity, E522L showed high sensitivity to NK cells; however, C831L showed resistance despite loss of HLA-class I expression. E522L expressed MHC class I chain related molecules A/B, but C831L did not. The transduction of the MHC class I chain related molecule A gene from E522L rendered C831L positive for expression and sensitive to NK cell cytotoxicity. Reconstruction of HLA-class I and MHC class I chain related molecules A expression could abrogate evasion from cellular attack by CTL and NK cells, and it may lead to a breakthrough in the development of cancer immunotherapy.