The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2α and ATF4 in Lung Cancer

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.

KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

“…4a, b ). As UPR triggering has been reported to up-regulate the expression of the immune checkpoint inhibitor PD-L1, 24 we next evaluated whether KSHV could do so in infected macrophages. As shown in Fig.…”

“…18,23 Therefore, in this study we next investigated whether KSHV infection could activate Ire1α and PERK branches of UPR in macrophages and if this effect increases the release of cytokines promoting tumorigenesis. Finally the expression of programmed death-ligand 1 (PD-L1), an immune check point inhibitor whose expression has been reported to be influenced by UPR in tumour cells 24 and to occur in KSHV-infected monocytes, 25 was evaluated in KSHV-infected macrophages and correlated with Ire1α and PERK activation. Unveiling the molecular mechanisms through which KSHV dysregulates the immune response could allow specific targeting of molecules promoting KSHV-associated malignancies.…”

IFN-γ-induced ER stress impairs autophagy and triggers apoptosis in lung cancer cells

“…One explanation could be that approximately one-third of melanoma and lung adenocarcinoma cell lines had inactivating mutations in the IFN-γ pathway components. 48 , 49 In addition, studies have shown that in some tumor tissues, the elF2α-ATF-4-CHOP signaling pathway is in a highly activated state, 50 which could undermine the effect of IFN-γ on ER stress. The precise underlying molecular mechanisms regarding the diverse response to IFN-γ in tumors could be more complex and require further investigation.…”

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

“…IRF1-deficient mouse models in colon cancer and melanoma showed inhibited tumor growth and upregulation of PD-L1 expression [ 37 ]. Moreover, PD-L1 expression is highly correlated with IRF1 in lung cancer [ 38 ]. IFN-γ-induced accumulation of IRF1 saturates STXBP6 and stimulates nuclear translocation of IRF1 that inhibits STXBP6 expression and triggers the migration of more IRF1 to the nucleus; this positive feedback loop regulates PD-L1 transcription [ 186 ].…”