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

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 senescence and 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 senescence can produce tumor control through non–cell autonomous mechanisms involving NK cell surveillance.

Source: ScienceNOW - December 20, 2018 Category: Science Authors: Ruscetti, M., Leibold, J., Bott, M. J., Fennell, M., Kulick, A., Salgado, N. R., Chen, C.-C., Ho, Y.-j., Sanchez-Rivera, F. J., Feucht, J., Baslan, T., Tian, S., Chen, H.-A., Romesser, P. B., Poirier, J. T., Rudin, C. M., de Stanchina, E., Manchado, E., S Tags: Immunology, Medicine, Diseases reports Source Type: news