Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.
Keywords: CTG; NK cells; cancer immunotherapy; cell tracker green; CTL; cytotoxic T lymphocyte; DCA; cytotoxic T lymphocytes; deoxy-ribonucleic acid; ERK5; dichloroacetate; dicholoroacetate; DNA; extracellular regulated kinase 5; FCS; fetal calf serum; mAb; glucose metabolism; magnetic cell separation; MHC-I; major histocompatibility complex class I; mRNA; messenger ribonucleic acid; NK; monoclonal antibody; MACS; natural killer; OXPHOS; oxidative phoshorylation; PBS; phosphate buffered saline; Poly I:C; polyinosinic: cytidilic acid; RNA; ribonucleic acid; sh; small hairpin; ρ° cells.