NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination
2018
Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that
mitogen-activated protein kinase(MAPK) and
cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of
KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes
retinoblastoma(RB) protein-mediated
cellular senescenceand activation of the immunomodulatory
senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor–α and
intercellular adhesion molecule–1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a
KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing
senescencecan produce tumor control through non–cell autonomous mechanisms involving NK cell surveillance.
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