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论文范文
Abstract：Introduction. The expression of programmed death 1 (PD1) and programmed death ligand 1 (PDL1) can be induced by the interferon (IFN)/signal transducer and activator of transcription (STAT) pathway. The PD1/PDL1 reverse signaling can activate the eukaryotic translation initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4) pathway which in turn regulates the expression of IFN regulatory factor (IRF) 7 and IFNα. The eIF2α/ATF4 pathway is responsible for the integrated stress response (ISR) of unfolded protein response (UPR) which can affect immune cell function in tumor microenvironment. Materials and Methods. The protein levels of PDL1, IRF1, IRF7, STAT1, STAT2, IFNAR1, eIF2α, and ATF4 in the normal and tumor tissues of 27 subjects with lung cancer were determined by Western blot. Results. The protein level of PDL1 was significantly correlated with those of IRF1, eIF2α, and ATF4 in the tissues of all subjects and the subgroup of squamous cell carcinoma but not in the normal tissue of adenocarcinoma. The protein levels of IRF1, eIF2α, and ATF4 were consistently correlated in the tumor tissues but to various extents in the normal ones. The protein level of PDL1 was not correlated with those of STAT1 and STAT2 in all the tissues. Conclusion. The PDL1 expression in lung cancer may be independent of STAT1 and STAT2. The PD1/PDL1 axis and UPR/ISR may be closely associated in the tumor tissues of lung cancer.
1. Introduction
Immune checkpoint inhibitors (ICI) like anti-PD1 (programmed death 1) or anti-PDL1 (programmed death ligand 1) antibodies are effective in treating various neoplasms, including lung cancer [1]. The first-line use of pembrolizumab, an anti-PD1 antibody, has longer progression-free and overall survival than platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC) with PDL1 expression at least 50% of tumor cells [2]. Similar findings have been observed in the second line of ICI in advanced NSCLC [3–5]. PDL1 tumor overexpression is associated with high response to anti-PD1 antibody in pretreated NSCLC [6]. The expression of PDL1 in lung cancer is important in selecting patient to treat with ICI. The proliferation and effector functions of T cell can be inhibited via the binding of PDL1 or PDL2 to PD1 on its surface [7]. PDL1 is expressed on many immune cells and nonimmune cells and is upregulated by proinflammatory cytokines such as interferon (IFN) γ and IL4 through signal transducer and activator of transcription 1 (STAT1) and IFN regulatory factor 1 (IRF1) [7, 8]. Tumor cells can induce the expression of PDL1 directly through the constitutive oncogenic pathways or indirectly with the help of T cell and the activation of IFN/STAT pathway [9]. Inflammatory cells, including activated T cells, contribute to the progression of malignancies [10]. In chronically activated T cells, IFNα causes prolonged PD1 transcription through the binding of activated IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1 and STAT2 in association with IRF9 [11], to the PD1 promoter [12]. The PD1/PDL1 axis is regulated by the IFN/STAT pathway (Figure 1). 
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