Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition

• Published in: Scientific reports Vol. 7; no. 1; pp. 7958 - 13
• Main Authors: Yang, Li, Shen, MingJing, Xu, Li Jun, Yang, Xiaodong, Tsai, Ying, Keng, Peter C., Chen, Yuhchyau, Lee, Soo Ok
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.08.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 13/51; 59; 59/5; 631/250/1933; 631/67/1612/1350; 692/4028/67/1612/1350; 692/420/755; 82; 82/1; 82/51; 96; A549 Cells; Animals; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - pharmacology; Apoptosis; B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - therapy; Cell culture; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Coculture Techniques; Cytotoxicity; Drug Resistance, Neoplasm; Extracellular signal-regulated kinase; Female; Humanities and Social Sciences; Humans; Immune response; Killer Cells, Natural - cytology; Killer Cells, Natural - metabolism; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Lymphocytes T; MAP Kinase Signaling System; Metabolic pathways; Mice; multidisciplinary; Natural killer cells; Neoplasms, Experimental; NKG2 antigen; PD-1 protein; PD-L1 protein; Science; Science (multidisciplinary); Signal transduction; Toxicity; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-08483-z

Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell’s function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro , as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.