Abstract
The drug resistance of first-line crizotinib therapy for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion non-small cell lung cancer (NSCLC) is inevitable. Whether the administration of immune checkpoint inhibitor (ICI) therapy is suitable for ROS 1 fusion NSCLCs or after the development of crizotinib resistance is still unknown. In this study, five different crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 cells were cultured. Ba/F3 cells expressing crizotinib sensitive ROS1 fusion and crizotinib resistant ROS1-G2032R mutation were used to explore the relationship between ROS1 fusion, ROS1-G2032R mutation and programmed death-ligand 1 (PD-L1) expression and the clinical potential of anti-PD-L1 ICI therapy. The 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 mutation. HCC78CR1-5 showed more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was remarkably higher in HCC78CR1-5 with ROS1 fusion upregulation than HCC78 primary cell. Furthermore, the expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated lower in Ba/F3 ROS1-G2032R resistant mutation than ROS1 fusion. Western blotting analysis showed the ROS1–SHP2 signaling pathway activation in HCC78CR1-5 cells, Ba/F3 ROS1 fusion and ROS1-G2032R resistant mutation. Mouse xenograft models with Ba/F3 ROS1 fusion showed more CD3+PD-1+ T cells both in blood and tissue, and more sensitivity than the cells with Ba/F3 ROS1-G2032R resistant mutation after anti-PD-L1 therapy. Our findings indicate that PD-L1 upregulation depends on ROS1 fusion more than ROS1-G2032R mutation. We share our insights of NSCLCs treatment management into the use of anti-PD-L1 ICI therapy in ROS1 fusion and not in ROS1-G2032R resistant mutation.
Highlights
At present, molecular targeted therapy is an important strategy for the treatment of non-small cell lung cancer (NSCLC) [1, 2]
To exclude the possibility that these results were due to nonspecific effects of crizotinib, we further investigated the effect of the phosphorylation of ROS1 and SHP2 on programmed death-ligand 1 (PD-L1) expression in Ba/F3 ROS1 fusion and Ba/F3 ROS1 G2032R cells by crizotinib, TPX-0005 and Lorlatinib at 1 um for ROS1 and SHP099 at 10 um for SHP2 (Figure 3E) after 6 h
Despite the lack of suitable biomarkers, accumulating evidence suggests that PDL1 is a good indicator for anti-PD-L1/PD-1 immune checkpoint inhibitor (ICI) therapy
Summary
Molecular targeted therapy is an important strategy for the treatment of non-small cell lung cancer (NSCLC) [1, 2]. As a new drug class, immunology checkpoint inhibitor (ICI) therapies, such as those involving anti-CTLA4 [3], anti-programmed cell death protein 1 (PD-1) [4] and anti-programmed death-ligand 1 (PD-L1) [5], show promise in the clinical treatment of several cancer types, especially melanoma and lung cancer [6], and they cause cancer to become a chronic disease by activating tumor immune cells in the tumor microenvironment (TME). In anti-PD-L1 therapy, the expression level of PD-L1 on tumor cells especially on tumor cells’ surface, is a key biomarker that correlates with the likelihood of an effective clinical response [7]. No study reported the relationship of ROS1 fusion with PD-L1 expression despite its high similarity with ALK
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