Abstract
PD-L1 is abnormally regulated in many cancers and is critical for immune escape. Fully understanding the regulation of PD-L1 expression is vital for improving the clinical efficacy of relevant anticancer agents. TGF-β plays an important role in the low reactivity of PD-1/PD-L1 antibody immunotherapy. However, it is not very clear whether and how TGF-β affects PD-L1 expression. In the present study, we show that TGF-β upregulates the expression of the transcriptional coactivator MRTF-A in non-small-cell lung cancer cells, which subsequently interacts with NF-κB/p65 rather than SRF to facilitate the binding of NF-κB/p65 to the PDL1 promoter, thereby activating the transcription and expression of PD-L1. This leads to the immune escape of NSCLC cells. This process is dependent on the activation of the TGF-β signaling pathway. In vivo, inhibition of MRTF-A effectively suppresses the growth of lung tumor syngrafts with enrichment of NK and T cells in tumor tissue. Our study defines a new signaling pathway that regulates the transcription and expression of PD-L1 upon TGF-β treatment, which may have a significant impact on research into the application of immunotherapy in treating lung cancer.
Highlights
Programmed cell death protein 1 (PD-L1) is the dominant inhibitory ligand of PD-1, can be detected on hematopoietic cells, including macrophages, dendritic cells (DCs) and stromal cells, and is upregulated on the surface of tumor cells[1,2]
To ascertain the role of PD-L1 in immune evasion induced by Transforming growth factor-β (TGF-β), the activity, and cytotoxicity of NK cells were determined in an in vitro assay in which NK-92 cells were cocultured with tumor cells with or without TGF-β treatment in the presence or absence of PD-1/PDL1 inhibitor 3
All these results indicate that TGF-β promotes the expression of PD-L1, which contributes to the immune escape of tumor cells
Summary
Programmed cell death protein 1 (PD-L1) is the dominant inhibitory ligand of PD-1, can be detected on hematopoietic cells, including macrophages, dendritic cells (DCs) and stromal cells, and is upregulated on the surface of tumor cells[1,2]. PD-1/PD-L1 antibodies have gained clinical approval for the treatment of melanoma, non-smallcell lung cancer (NSCLC), renal cell carcinoma (RCC), Hodgkin’s lymphoma, urothelial carcinoma, and gastric cancer[10]. Even in these tumor types, only a fraction of patients show objective clinical responses (e.g., to the anti-PD-1 monoclonal antibody nivolumab; complete response 0.7%, partial response 19.3%), among whom 15–35% will develop drug resistance[11]. Given that the expression of PD-L1 on tumor cells has predictive value for the response to antibody-based monotherapies in many studies, especially those on melanoma and NSCLC6,16,17, and because inhibition of PD-L1 expression in tumor cells in combination with anti-PD-L1 or anti-PD-1 antibody immunotherapy can effectively suppress the growth of various tumors[18,19], fully understanding the regulation of PD-L1 expression is vital for improving the clinical efficacy of relevant anticancer agents
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