Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses

Wang, Wei-Bei; Yen, Men‐Luh; Liu, Ko‐Jiunn; Hsu, Pei‐Ju; Lin, Ming‐Hong; Chen, Peimin; Sudhir, Putty‐Reddy; Chen, Chein‐Hung; Chen, Chung-Hsuan; Sytwu, Huei-Kang; Yen, B. Linju

doi:10.1016/j.stemcr.2015.07.013

Cited by 63 publications

(54 citation statements)

References 66 publications

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“…For cancer cells with EGFR mutation, PD-L1 expression should, theoretically, be upregulated via activation of stat-3, PI3K-AKT or RAS-RAF-MAPK pathways by constant signals from EGFR. [31][32][33][34][35][36][37] Therefore, the case with up-regulated PD-L1 expression by EGFR mutation would be included in pulmonary adenocarcinomas. However, our findings appear to negate the main contribution of EGFR mutation of tumour cells towards PD-L1 expression intensity of pulmonary adenocarcinomas, although a relationship between PD-L1 expression and oncogene addiction including various signal pathway cascades remains to be elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors

et al. 2016

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IntroductionThe contribution of programmed cell death ligand-1 (PD-L1) immune checkpoint molecule toward progression of non-small cell lung cancer (NSCLC) has not yet been elucidated, in part, because of lack of a standardised method to evaluate PD-L1 expression. In this study, we developed a novel method for the evaluation of PD-L1 expression on NSCLC cells and examined its correlation with clinicopathological characteristics.MethodsAfter immunohistochemical examination of PD-L1 expression for surgically resected pulmonary adenocarcinomas (n=106), based on the findings that PD-L1 are consistently expressed on alveolar macrophages, PD-L1 staining intensity of tumour cells was classified into four levels relative to PD-L1 staining intensity in alveolar macrophages; PD-L1 expression scores (range, 0–300) were semiquantitatively assessed. An analysis of statistical association between PD-L1 expression score and clinicopathological characteristics was performed.ResultsAlmost all of the alveolar macrophages in the specimens were moderately to strongly stained with PD-L1, serving as an internal positive control in the immunohistochemistry of PD-L1. PD-L1 expression score (median, 52.3) was significantly higher in tumours with G2/3 differentiation than in those with G1 (p=0.022) and higher in those with lymphatic invasion than in those without invasion (p=0.032). Postoperative relapse-free survival was significantly shorter in patients with a high PD-L1 expression score than in those with low PD-L1 expression score (p=0.035). Smoking habits, histological subtype, and epidermal growth factor receptor mutation status were not associated with PD-L1 expression score.ConclusionsGiven the heterogeneous distribution of PD-L1 expression in pulmonary adenocarcinoma cells, the scoring of PD-L1 expression on tumour cells relative to that in alveolar macrophages appears to be a valid indicator of PD-L1 status of patients with pulmonary adenocarcinomas, demonstrating a significant correlation with several factors associated with tumour progression.

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Section: Discussionmentioning

confidence: 99%

Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors

et al. 2016

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“…It was shown to limit Th1 and Th17 responses in mice via APC and mesenchymal stem cell activation (Caruso et al, 2009;Kleinschek et al, 2007;Liu et al, 2015;Wang et al, 2015). Since psoriasis is regarded as driven by Th1/Th17 cells, the overexpression of IL-17E was unexpected and puzzling.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis

Senra

Stalder

Martínez

et al. 2016

Journal of Investigative Dermatology

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Psoriasis is a chronic inflammatory skin disorder effectively treated by blocking IL-17RA, a receptor chain used by several IL-17 family members, including IL-17E. Although IL-17A is critically involved in the pathogenesis of psoriasis, the contribution of IL-17E remains unknown. Here we show that IL-17E(+) cells are more abundant than IL-17A(+) cells in lesional psoriatic skin. IL-17E synthesis is increased in keratinocytes within psoriatic plaques, and macrophages having a mixed M1/M2 phenotype represent an important proportion of the IL-17E(+) cells infiltrating the dermis. Mechanistically, macrophages do not synthetize but rather take up IL-17E via receptor-mediated clathrin-dependent endocytosis. Furthermore, monocyte-derived macrophages in vitro polarized in M2, but not M1, express the IL-17E receptor and respond to IL-17E by preferentially producing inflammatory cytokines and chemokines involved in neutrophil recruitment. Remarkably, IL-17E expression in lesional psoriatic skin correlates with the number of neutrophils while being inversely proportional to the number of infiltrating T cells. These data provide strong evidence for a proinflammatory role of keratinocyte-derived IL-17E in psoriasis, possibly via macrophage activation.

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“…In human MSC, the reported pathways of immune suppression by MSC include the indoleamine 2,3-deoxygenase (IDO) [21,22], cyclooxygenase [23][24][25], TGF-b [26], soluble IL-1Ra [27,28], soluble MHC [29,30], and the PD-L1 pathways [31,32]. In general however, the IDO-dependent pathway is considered the primary mechanism of human MSC suppression of activated immune effector cells [21].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Suppression Utilized by Canine Adipose and Bone Marrow-Derived Mesenchymal Stem Cells

ChowLyndah

JohnsonValerie

CoyJonathan

et al. 2017

Stem Cells and Development

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Mesenchymal stem cells (MSCs) from rodents and humans have been shown to suppress T cells by distinct primary pathways, with nitric oxide (NO)-dependent pathways dominating in rodents and indoleamine 2,3-deoxygenase (IDO)-dependent pathways dominating in humans. However, the immune suppressive pathways utilized by canine MSC have not been thoroughly studied, nor have bone marrow-derived MSC (BM-MSC) and adipose-derived MSC (Ad-MSC) been directly compared for their immune modulatory potency or pathway utilization. Therefore, canine BM-MSC and Ad-MSC were generated in vitro and their potency in suppressing T cell proliferation and cytokine production was compared, and differential gene expression. Mechanisms of T cells suppression were also investigated for both MSC types. We found that BM-MSC and Ad-MSC were roughly equivalent in terms of their ability to suppress T cell activation. However, the two MSC types used both shared and distinct biochemical pathways to suppress T cell activation. Ad-MSC utilized TGF-b signaling pathways and adenosine signaling to suppress T cell activation, whereas BM-MSC used cyclooxygenase, TGF-b and adenosine signaling pathways to suppress T cell activation. These results indicate that canine MSC are distinct from human and rodent MSC terms of their immune suppressive pathways, relying primarily on cyclooxygenase and TGF-b pathways for T cell suppression, rather than on NO or IDO-mediated pathways.

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Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses

Cited by 63 publications

References 66 publications

Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors

Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors

Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis

Mechanisms of Immune Suppression Utilized by Canine Adipose and Bone Marrow-Derived Mesenchymal Stem Cells

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