Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective

Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. The well-established antitumor activity of NK cells is strictly dependent on the expression of ligands for NK cell-activating receptors on tumor cell surfaces. The molecular mechanisms underlying the upregulation of ligands for NK cell-activating receptors on tumor cells mainly depend on signaling pathways activated upon DNA damage induced by many different cytotoxic drugs. NK cell adoptive transfer in autologous or allogeneic settings represents a promising anticancer immunotherapeutic approach that has been tested in different clinical trials. The therapeutic efficacy of NK cell adoptive transfer may be dampened by downregulation of ligands for NK cell-activating receptors. A major immune-evasion mechanism adopted by most aggressive cancer cells. Many cytotoxic drugs utilized to treat cancer patients have been reported to upregulate the expression of ligands for NK cell-activating receptors in tumor cells, thus enhancing NK cell-mediated killing. Some of these drugs are excellent candidates for the design of new cancer immunotherapy protocols based on the combination of chemotherapy with allogeneic or autologous NK cell adoptive transfer.