Targeting the tumor microenvironment to improve natural killer cell-based immunotherapies: On being in the right place at the right time, with resilience.

Natural killer (NK) cell immunotherapies that target solid tumors require NK cells in the proper place, at the right time, with optimal function and a susceptible target cell. Basic research and clinical correlative studies have provided evidence, for certain malignancies, that intratumoral NK cells delay tumor progression. Whether NK cells exert anti-tumor effects for solid tumors is determined by a number of factors including homing and activating receptor expression by NK cells themselves and the sensitivity of tumor cells to be targets of NK cell cytolysis, which depends on the chemokine and NK cell-inhibitory and activating receptor ligand expression by tumor cells. Chemotherapeutic agents that increase NK cell-activating receptor ligands on tumor cells have been clinically promising as well as ectopic gene expression in NK cells with factors that overcome the suppressive mechanisms of the tumor microenvironment (TME). Identifying agents that decrease myeloid-derived suppressor cells (MDSC) or T regulatory (Treg) cell frequencies or function would be important to co-administer with adoptively transferred NK cells to ameliorate immunosuppressive TMEs. Thus, studies indicate that critical factors for NK cell immunotherapies targeting the TMEs are: being in the right place at the right time, with resilience.