Abstract 1520: IL-6 up-regulates pd-l1 and facilitates lung cancer escape from NK cell immune function through its downstream MEK-ERK signaling

Abstract

Abstract Background: We previously reported that IL-6 was associated with therapy resistance to radiotherapy and cisplatin chemotherapy, the two most common treatments for non-small cell lung cancer (NSCLC). Emerging in vivo evidence shows that natural killer (NK) cells have an important role in immune defense. In this study, we examined the role of IL-6 modulation in lung cancer PD-L1 expression and the impact on NK cell cytotoxicity. We also revealed the key molecular signaling pathway involved in this process, which serves as the potential therapeutic target to improve clinical lung cancer treatments. Methods: We examined the prevalence of IL-6 in tumors of NSCLC in immunohistochemical staining. The susceptibility of IL-6 expressing scramble control (A549sc and H157sc) cells and IL-6 knocked down (A549siIL-6 and H157siIL-6) cells were investigated in in vitro and in vivo human tumor xenograft studies in mice. In in vivostudies, tumors were developed by luciferase tagged A549siIL-6 vs. A549sc cell injection, and primary human NK cells were injected intravenously at the early stage of tumor development. IL-6 regulation of PD-L1 at the transcriptional level was investigated and NK cell binding to tumor cells was also examined. Results: We found the ubiquitous presence of IL-6 in NSCLC. We found IL-6 expressing lung cancer cells were more resistant to NK cell cytotoxicity than IL-6 knocked-down cells. In addition, we found higher expressions of programmed death receptor 1 ligand (PD-L1) in IL-6 expressing lung cancer cells than IL-6 knocked-down cells. In excised human tumor xenografts and in human NSCLC tumors, co-localization of IL-6 signaling and PD-L1 expression was observed. Furthermore, we discovered that IL-6 promoted PD-L1 expression at the transcriptional level via the regulation of its downstream MEK/Erk signaling pathway. In addition, we found that IL-6-MEK/Erk signaling also contributed to diverting NK cells away from binding to tumor cells. Conclusions and Impact: In conclusion, we found that IL-6 develops the resistance to NK cell actions by inducing PD-L1 in NSCLC cells and diverts NK cells away from tumor cells via its downstream MEK/Erk signaling. NK cell-mediated immune function plays an important role in cancer surveillance, invasion, and metastasis, but its role in lung cancer is not clear. In in vivo studies, we proved the importance of NK cell-mediated immune reaction. Our discovery of revealing the IL-6 downstream signaling, MEK/Erk, in triggering the PD-L1 up-regulation and in blocking NK cell binding with lung cancer cells is novel. Data from this investigation support that blocking MEK/Erk signaling pathway has the potential to enhance NK cell immune function to NSCLC by overcoming IL-6 mediated NK cell resistance. Citation Format: Soo Ok Lee, Rongying Zhu, Xiang Xue, Donglai Cchen, Shanzhou Duan, Mingjing Shen, Feng Chen, Ying Tsai, Peter Keng, Yongbing Chen, Yuhchyau chen. IL-6 up-regulates pd-l1 and facilitates lung cancer escape from NK cell immune function through its downstream MEK-ERK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1520.