NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination.
Marcus RuscettiJosef LeiboldMatthew J BottMyles FennellAmanda KulickNelson R SalgadoChi-Chao ChenYu-Jui HoFrancisco J Sanchez-RiveraJudith FeuchtTimour BaslanSha TianHsuan-An ChenPaul B RomesserJohn T PoirierCharles M RudinElisa de StanchinaEusebio ManchadoCharles J SherrScott W LowePublished in: Science (New York, N.Y.) (2019)
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.
Keyphrases
- nk cells
- public health
- cell death
- mouse model
- single cell
- dna damage
- endothelial cells
- wild type
- signaling pathway
- emergency department
- cell therapy
- rheumatoid arthritis
- escherichia coli
- bone marrow
- quality improvement
- drug induced
- small molecule
- adverse drug
- cancer therapy
- cystic fibrosis
- newly diagnosed
- cell cycle arrest
- cell migration