Abstract
BackgroundProgrammed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.MethodsBioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.ResultsBased on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.ConclusionsCXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.
Highlights
Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments
Targeted drugs prolong the survival of patients with advanced gastric cancer (GC) by more than a year, the 5-year survival rate is less than 20% [2, 3]
The hypothesis that CXCL9/10/11-CXCR3 signaling upregulated PD-L1 expression was established by bioinformatics GSEA analysis Using the the Cancer Genome Atlas (TCGA), GSE15459 and GSE62254 datasets, the pathways ranked as the “significant enrichment genes” were shown in Fig. 1a, b and Additional file 1: Table S1, Additional file 2: Table S2, Additional file 3: Table S3
Summary
Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Cancer immunotherapy has shown major advancements during the past few years Immune checkpoints such as cytotoxic T-lymphocyte-associated antigen (CTLA-4) and programmed death-ligand 1 (PD-L1) can suppress the activity of T-lymphocytes, which could recognize and eliminate cancer antigens [4]. In 2014, the PD-1 monoclonal antibody pembrolizumab targeting the PD-L1/PD-1 signaling pathway, had shown significant clinical effect in patients with high PD-L1 expression in advanced melanoma and non-small cell lung cancer. It was approved by the US FDA as the first-line treatment for advanced melanoma in 2015 [8].
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