Data Availability StatementThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request. 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 YZ9 and invasiveness, YZ9 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. reported that tumor specific T-cell responses can select tumor-associated antigen-negative cells and variants Rabbit Polyclonal to MRGX3 resistant to CTLs (4,5). We previously reported that the reorganization of the actin cytoskeleton may be used by tumor cells as a strategy to promote their resistance to CTL-mediated lysis (6). Therefore, it is likely that tumor variants resistant to T cells will emerge, most frequently in the context of effective immunotherapies (7). Consequently, even if a strong and sustained cytotoxic response is induced, there remain complex issues, such as tumor evasion and selection of tumor-resistant variants. Natural killer (NK) cells are also involved in the control of tumor progression (8,9) and several reports have indicated that solid tumor infiltration by NK cells is a favorable prognostic marker (10C12). NK cell-mediated cytotoxic activity can eliminate tumor cells that have evaded CD8+ T cells through loss of antigen or MHC class I molecules. Moreover, through their secretion of cytokines or by mutual activation links established with dendritic cells (DCs) (13C15), NK cells can positively modulate adaptive immune responses against tumor cells and their susceptibility to CD8+ T cells (16). However, it should be noted that and studies demonstrated a poor or defective activity of NK cells in cancer, as well as resistance of tumor cells to NK cell-mediated lysis. Mechanistically, the imbalance between activating and inhibitory signals, which may be caused by low expression of ligands to activating receptors and high expression YZ9 of ligands to inhibitory receptors of NK cells on tumor cells, was suggested as being one of the major mechanisms underlying the poor anticancer activity of NK cells (17). Although NK cells have been established as the main effectors of antitumor immune response, their putative role on YZ9 the emergence of tumor cytotoxic resistant variants remains poorly understood. Evidence of NK cell immunoediting was reported by studies using NK-deficient models, and demonstrated how exposure to NK cells causes modification of cancer immunogenicity to allow survival and progression of the tumor clone in an immunocompetent environment. In addition, Moretta reported that NK cells play an important regulatory role by selectively editing DCs YZ9 during the course of the immune response, and that NK cell-mediated killing of immature DCs results in selection of immunogenic DCs during the initiation of anticancer immune responses (18). While several studies have revealed the contribution of adaptive and innate immunity to cancer immunoediting (1,5,19C25), whether the innate immune system can suppress tumor formation without adaptive immunity remains elusive. We previously used a lung cancer model to study the emergence of tumor resistance following specific cytotoxic T lymphocyte (CTL) selection pressure (6). We also described various mechanisms of resistance to NK cells that may differ between tumor types, tumor aggressiveness and environmental contexts.