NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination

Accumulating evidence suggests that molecularly targeted therapies, which were originally developed to target the underlying cell autonomous genetic drivers of tumorigenesis, can provoke tumor specific immune responses. Using immunocompetent mouse models of KRAS mutant lung adenocarcinoma, we show that a combination of MEK and CDK4/6 inhibitors can induce natural killer (NK) cell immune surveillance that is necessary for its full anti-tumor effect. Mechanistically, we show that the drug combination – but neither agent alone – drives RB-mediated cellular senescence induction leading to potent cell cycle arrest and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). This, in turn, leads to an increase in tumor-specific NK cell ligand expression and secretion of TNF-α that provokes NK cell-mediated targeting of senescent tumor cells, culminating in tumor regressions and long-term survival in genetically engineered mouse models of lung cancer. These studies identify a means and method of invoking a unique form of NK cell mediated immune surveillance in lung tumors through molecularly targeted therapies that induce senescence.