Selection of tumor-resistant variants following sustained natural killer cell-mediated immune stress

Resistance of tumor cells to cell-mediated cytotoxicity remains an obstacle to the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell-mediated cytotoxicity, resistant variants were selected following long-term natural killer (NK) cell selection pressure. It was observed that these variants were resistant to NK cell-mediated lysis, but were sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance appeared to be dependent, at least partly, on an alteration of target cell recognition by NK effector cells, but did not appear to involve any alterations in the expression of KIR, DNAM1 or NKG2D ligands on resistant cells, nor the induction of protective autophagy. In the present study, in order to gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cell-mediated cytotoxicity, a comprehensive analysis of the variant transcriptome was conducted. Comparative analysis identified an expression profile of genes that best distinguished resistant variants from parental sensitive cancer cells, with candidate genes putatively involved in NK cell-mediated lysis resistance, but also in adhesion, migration and invasiveness, including upregulated genes, such as POT1, L1CAM or ECM1, and downregulated genes, such as B7-H6 or UCHL1. Consequently, the selected variants were not only resistant to NK cell-mediated lysis, but also displayed more aggressive properties. The findings of the present study emphasized that the role of NK cells may span far beyond the mere killing of malignant cells, and NK cells may be important effectors during cancer immunoediting.