AUTHOR=Cai Liangliang , Duan Jianchun , Qian Li , Wang Zhijie , Wang Shuhang , Li Sini , Wang Chao , Zhao Jie , Zhang Xue , Bai Hua , Wang Jie 

TITLE=ROS1 Fusion Mediates Immunogenicity by Upregulation of PD-L1 After the Activation of ROS1–SHP2 Signaling Pathway in Non-Small Cell Lung Cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.527750

DOI=10.3389/fimmu.2020.527750

ISSN=1664-3224

ABSTRACT=The drug resistance of first line Crizotinib molecularly targeted therapy for ROS1 fusion non-small cell lung cancer (NSCLC) was still inevitable. Whether it is suitable to give immunology checkpoint inhibitor (ICI) therapy or not in ROS1 fusion NSCLCs, or even after molecularly targeted therapy drug resistance, is still unknown. Five different Crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 were cultured. Ba/F3 cells expressing sensitive ROS1 fusion and ROS1 G2032R with Crizotinib resistance mutation G2302R were constructed to explore the relationship between ROS1 fusion, ROS1 G2032R resistance mutation and PD-L1 expression. Signaling pathway net was compared between HCC78 and HCC78CR1-5 cells using RNA Sequencing. Anti-PD-L1 ICI therapy was performed on mouse xenograft models with Ba/F3 ROS1 fusion or ROS1 G2032R. HCC78CR1-5 show more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was higher in HCC78CR1-5 with ROS fusion upregulation than HCC78 primary cell. Furthermore, expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated in Ba/F3 ROS1 fusion while lower in Ba/F3 ROS1 G2302R. The western blotting analysis shows that the ROS1-SHP2 signaling pathway activation in ROS1 fusion cells. Mouse xenograft models with Ba/F3 ROS1 fusion shows more sensitive than the Ba/F3 ROS1 G2302R resistance mutation after anti-PD-L1 therapy. Our findings that PD-L1 upregulation depending on ROS1 fusion, while less in ROS1 G2302R resistance mutation. We share our insights into the anti-PD-L1 ICI therapy during the primary ROS1 fusion Crizotinib sensitive or ROS1 G2302R acquire Crizotinib drug resistance.