IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma

Zhang, Wenjie; Liu, Yang; Yan, Zhongyi; Yang, Hui; Sun, Wei; Yao, Yongliang; Chen, Yun; Jiang, Runqiu

doi:10.1136/jitc-2019-000285

Cited by 104 publications

(81 citation statements)

References 52 publications

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“…In prostate cancer, the IL-6-JAK-STAT3 pathway promoted PD-L1 expression and led to the resistance to immune killing [ 50 ]. Moreover, in hepatocellular carcinoma, increased IL-6 activated the STAT3/c-MYC/miR-25-3p pathway, which resulted in the decreased protein tyrosine phosphatase receptor type O (PTPRO) [ 51 ]. The downregulated PTPRO-enhanced PD-L1 expression by deregulating the activation of JAK2-STAT1/3 [ 51 ].…”

Section: Transcriptional Regulationmentioning

confidence: 99%

“…Moreover, in hepatocellular carcinoma, increased IL-6 activated the STAT3/c-MYC/miR-25-3p pathway, which resulted in the decreased protein tyrosine phosphatase receptor type O (PTPRO) [ 51 ]. The downregulated PTPRO-enhanced PD-L1 expression by deregulating the activation of JAK2-STAT1/3 [ 51 ]. Furthermore, the glioblastoma-derived IL-6 could induce the local and systemic myeloid PD-L1 expression by STAT3 phosphorylation [ 52 ].…”

Section: Transcriptional Regulationmentioning

confidence: 99%

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Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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Section: Transcriptional Regulationmentioning

confidence: 99%

Section: Transcriptional Regulationmentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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“…We then analyzed BM levels of IL-6, the main MM pro-survival factor ( 36 ), which is also involved in PD-L1 up-regulation on monocytes ( 37 ) and recently described as predictor of response to PD-L1/PD-1 inhibitors in NSCLC patients ( 38 ). Our data confirmed higher IL-6 BM levels in patients with active myeloma compared with SMM, however no correlation emerged with PD-L1/PD-1 expression.…”

Section: Discussionmentioning

confidence: 99%

PD-L1/PD-1 Pattern of Expression Within the Bone Marrow Immune Microenvironment in Smoldering Myeloma and Active Multiple Myeloma Patients

et al. 2021

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BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

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“…IL-6 is one of the most important proinflammatory cytokines and is massively released by APCs in the hyper-acute phase of COVID-19 and STEMI upon pathogen- or danger-associated molecular pattern detection ( 67 ). This product plays a decisive role in inducing immediate (and sometimes excessive) innate immunity response, but on the other hand it activates PD-L1 expression of APCs ( 68 ). If unregulated, this dual mechanism can end up with disproportionate predominance of hyper-activated innate immunity over adaptive immunity depressed by lymphocyte apoptosis.…”

Section: Attenuation Of the Immune Reaction To Avoid Excessive Tissue Damage And Restore Hemostasismentioning

confidence: 99%

Unraveling the thread of uncontrolled immune response in COVID-19 and STEMI: an emerging need for knowledge sharing

Ríos‐Navarro

Dios

Forteza

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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The outbreak of severe acute respiratory syndrome coronavirus 2 that first emerged in Wuhan in December 2019 has resulted in the devastating pandemic of coronavirus disease 2019, creating an emerging need for knowledge sharing. Meanwhile, myocardial infarction is and will probably remain the foremost cause of death in the western world throughout the coming decades. Severe deregulation of the immune system can unnecessarily expand the inflammatory response and participate in target and multiple organ failure, in infection but also in critical illness. Indeed, the course and fate of inflammatory cells observed in severe ST-elevation myocardial infarction (neutrophilia, monocytosis and lymphopenia) almost perfectly mirror those recently reported in severe coronavirus disease 2019. A pleiotropic proinflammatory imbalance hampers adaptive immunity in favor of uncontrolled innate immunity and is associated with poorer structural and clinical outcomes. The goal of the present review is to gain greater insight into the cellular and molecular mechanisms underlying this canonical activation and downregulation of the two arms of the immune response in both entities, to better understand their pathophysiology as well as to open the door to innovative therapeutic options. Knowledge sharing can pave the way for therapies with the potential to significantly reduce mortality in both infectious and non-infectious scenarios.

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IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma

Cited by 104 publications

References 52 publications

Regulation of PD-L1 expression in the tumor microenvironment

Regulation of PD-L1 expression in the tumor microenvironment

PD-L1/PD-1 Pattern of Expression Within the Bone Marrow Immune Microenvironment in Smoldering Myeloma and Active Multiple Myeloma Patients

Unraveling the thread of uncontrolled immune response in COVID-19 and STEMI: an emerging need for knowledge sharing

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