Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma

He, Gaixia; Zhang, Henghui; Zhou, Jinxue; Wang, Beibei; Chen, Yanhui; Kong, Yaxian; Xie, Xingwang; Wang, Xueyan; Fei, Ran; Wei, Lai; Chen, Hongsong; Zeng, Hui

doi:10.1186/s13046-015-0256-0

Cited by 199 publications

(191 citation statements)

References 36 publications

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“…Interestingly, inflammatory factors were not in equivalent levels in the intratumoral and peritumoral sites. IL-1β, GM-CSF, G-CSF, TnF-α, and IL-6 were significantly increased in tumor tissues compared with adjacent non-tumor tissues (55,56). IL-6 and IL-8 released from myofibroblasts were found to upregulate S100A8/A9 in tumor-infiltrated myeloid cells (57).…”

Section: Discussionmentioning

confidence: 99%

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Zha

Sun

et al. 2016

Oncology Reports

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Abstract.Previous studies have shown that S100 calcium-binding protein A8 (S100A8) contributes to the survival and migration of colorectal cancer (CRC) cells. However, whether S100A8 participates in the progression and metastasis of CRC via the regulation of macrophages in the tumor inflammatory microenvironment remains unknown. In this study, phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. MTT assay, western blot analysis, immunofluorescence staining, semi-quantitative RT-PCR (semi-PCR), quantitative real-time PCR (qPCR), Gaussia luciferase activity assay and ELISA were performed to analyze the roles and molecular mechanisms of S100A8 in the modulation of macrophages. MTT assay, flow cytometric analysis, Hoechst staining, wound healing and Transwell migration assay were used to test the effect of S100A8 on the viability and migration of CRC cells co-cultured with macrophages in the inflammatory microenvironment. We found that THP-1 monocytes were induced by PMA and differentiated to macrophages. S100A8 activated the NF-κB pathway in the macrophages and promoted the expression of miR-155 and inflammatory cytokines IL-1β and TNF-α in the inflammatory microenvironment mimicked by lipopolysaccharides (LPS). Furthermore, S100A8 contributed to augment the migration but not the viability of the CRC cells co-cultured with the macrophages in the inflammatory microenvironment. Altogether, our study demonstrated that S100A8 facilitated the migration of CRC cells in the inflammatory microenvironment, and the underlying molecular mechanisms may be partially attributed to the overexpression of miR-155, IL-1β and TNF-α through activation of the NF-κB pathway in macrophages. IntroductionColorectal cancer (CRC), for which distant metastasis accounts for the leading cause of cancer mortality, is one of the most malignant gastrointestinal carcinomas worldwide (1). The pathogenesis of CRC is a complex process and involves environmental influences, genetic alterations, and the host immune system and their interactions. The formation of an inflammatory microenvironment also plays a pivotal role in the development of CRC (2). The host microenvironment is comprised of numerous infiltrating immune cell types and resident tumor cells. Among the immune cells, macrophages play an indispensable role. For instance, macrophage infiltration in colon tissue has been observed in both inflammatory bowel disease (IBD) and CRC (4), and the cytokines secreted by macrophages under certain conditions have directly or indirectly stimulated inflammation and tumor progression (5,6). Although great progress has been made, the interactions and the molecular mechanisms between CRC and the inflammatory microenvironment remain unknown. S100A8 (calgranulin A or S100 calcium-binding protein A8) is a member of the low-molecular calcium binding S100 protein family. It also belongs to the family of damage-associated molecular patterns (DAMPs). Studies have shown that S100A8 plays an important role in regul...

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Section: Discussionmentioning

confidence: 99%

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Zha

Sun

et al. 2016

Oncology Reports

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“…Moreover, a study recently indicated that a high level of peritumoral neutrophil infiltration and neutrophil-to-lymphocyte T cell ratio (pNLR) correlated with poor patient survival after curative resection. This study also showed that peritumoral neutrophils negatively regulated adaptive immunity via the PD-L1/PD-1 signaling pathway in HCC patients [31]. Accordingly, we speculated that PD-L1 expression in peritumoral infiltrating immune cells may also be a poor prognostic marker partly resulting from peritumoral infiltration of PD-L1 positive neutrophil interacting with PD-1 positive CD8 + T cells to inhibit and destroy T-cell-mediated antitumor immunity.…”

Section: Discussionmentioning

confidence: 70%

Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma

Dai

Xue

et al. 2017

Translational Oncology

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BACKGROUND: Recurrence or metastasis of hepatocellular carcinoma (HCC) is mainly intrahepatic after curative resection, demonstrating that the peritumoral environment is important but often neglected. Programmed death ligand 1 (PD-L1) in intratumoral liver tissues is a poor prognosis factor whose impact is removed after curative resection. However, PD-L1 expression remains in the peritumoral liver tissues and its distribution and prognostic value are still not clear. METHODS: We assessed the expression of PD-L1 by immunohistochemistry in peritumoral liver tissues from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: We found PD-L1 positive expression in 31.11% (28/90) of peritumoral tissues. Peritumoral PD-L1 expression was associated with a significantly worse overall survival (OS) (P = .000) and disease-free survival (DFS) (P = .001) compared to the negative expression group. Additionally, peritumoral PD-L1 positivity significantly correlated with vascular invasion and a lower albumin level (≤35 g/L). Univariate and multivariate Cox regression models both revealed peritumoral PD-L1 as an independent prognostic factor for OS (HR = 2.853, P = .002) and DFS (HR = 2.362, P = .003). The prognostic value of PD-L1 positivity was validated in the independent data set. CONCLUSIONS: Our data suggest PD-L1 expression in peritumoral hepatocytes is an independent prognostic factor for OS and DFS. This implies that future anti-cancer therapy should target not only residual tumor cells but also the “soil” for promoting tumor growth. Peritumoral PD-L1 could be a good target for adjuvant therapy after hepatectomy.

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“…Levels of immunosuppressive cytokines IL‐10 and TGF‐β are upregulated in HCC patients at the same time as pro‐inflammatory IFN‐γ levels are downregulated 88 . An increased percentage of circulating and tumour‐infiltrating CD8 + T cells express PD‐1 while tumour cells and tumour‐associated monocytes and neutrophils express upregulated PD‐L1 and CD47 levels in HCC patients 89 , 90 , 91 , 92 . The numbers of myeloid‐derived suppressor cells are also elevated in HCC patients 88 , 93 .…”

Section: Subversion Of the Immune System During Hcc Developmentmentioning

confidence: 99%

“…88 An increased percentage of circulating and tumourinfiltrating CD8 + T cells express PD-1 while tumour cells and tumourassociated monocytes and neutrophils express upregulated PD-L1 and CD47 levels in HCC patients. [89][90][91][92] The numbers of myeloid-derived suppressor cells are also elevated in HCC patients. 88,93 Furthermore, activation of the c-Myc oncogene switches on PD-L1 and CD47 expression in hepatocytes, 94 raising the possibility that oncogenes may directly regulate PD-L1 levels to subvert surveillance.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Immune checkpoint inhibition: prospects for prevention and therapy of hepatocellular carcinoma

et al. 2017

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The global prevalence of liver cancer is rapidly rising, mostly as a result of the amplified incidence rates of viral hepatitis, alcohol abuse and obesity in recent decades. Treatment options for liver cancer are remarkably limited with sorafenib being the gold standard for advanced, unresectable hepatocellular carcinoma but offering extremely limited improvement of survival time. The immune system is now recognised as a key regulator of cancer development through its ability to protect against infection and chronic inflammation, which promote cancer development, and eliminate tumour cells when present. However, the tolerogenic nature of the liver means that the immune response to infection, chronic inflammation and tumour cells within the hepatic environment is usually ineffective. Here we review the roles that immune cells and cytokines have in the development of the most common primary liver cancer, hepatocellular carcinoma (HCC). We then examine how the immune system may be subverted throughout the stages of HCC development, particularly with respect to immune inhibitory molecules, also known as immune checkpoints, such as programmed cell death protein-1, programmed cell death 1 ligand 1 and cytotoxic T lymphocyte antigen 4, which have become therapeutic targets. Finally, we assess preclinical and clinical studies where immune checkpoint inhibitors have been used to modify disease during the carcinogenic process. In conclusion, inhibitory molecule-based immunotherapy for HCC is in its infancy and further detailed research in relevant in vivo models is required before its full potential can be realised.

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Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma

Cited by 199 publications

References 36 publications

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma

Immune checkpoint inhibition: prospects for prevention and therapy of hepatocellular carcinoma

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