Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions

Yan, Zhidong; Zhuansun, Yongxun; Liu, Guirong; Chen, Rui; Li, Jianguo; Ran, Pixin

doi:10.1016/j.imlet.2014.09.013

Cited by 45 publications

(35 citation statements)

References 38 publications

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“…Although the passage-dependent reduction of CD274 expression in hUCB-MSCs did not reach statistical significance, 5 of 25 lots of hUCB-MSCs showed dramatically decreased CD274 expression at a late passage (supplemental online Table 4). Because CD274 has been reported to be involved in the hypoimmunogenic features of MSCs [34,35], these late-passage cells may not be suitable for transplantation as a result of the lack of these properties. However, the overall expression levels of CD274 were in fact relatively low both in early-and late-passage naïve hUCB-MSCs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

Jin

Kwon

Kim

et al. 2016

Stem Cells Translational Medicine

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CD146 expression is gradually decreased during the long‐term expansion of human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs) in culture, and enforced CD146 downregulation accelerated senescence in hUCB‐MSCs, which affected their multilineage differentiation potential, growth, and stemness. These data indicate a possible role for CD146 in inhibiting senescence in hUCB‐MSCs, which may occur via the regulation of Bmi‐1, Id1, and Twist1 expression. CD146 may be a novel marker for predicting senescence in hUCB‐MSCs, and it could be valuable in quality‐control assessments and for improving the therapeutic potential of hUCB‐MSC‐based therapy.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

Jin

Kwon

Kim

et al. 2016

Stem Cells Translational Medicine

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“…It is well known that PD-1 or PD-L1 expression within the tumour lesion and microenvironment in general are not su cient surrogate markers for treatment response in patients receiving checkpoint inhibition in HCC 14 . Recently, several study groups emphasized that mesenchymal stem cells suppress in ammation and inhibit the immune response by the PD-1/PD-L1 axis 17,18 . To our knowledge there is only minor or no clinical evidence in large HCC cohorts to support the e cacy of immune checkpoint inhibitors in CSC-predominant subtypes of HCC.…”

Section: Discussionmentioning

confidence: 99%

Clinical Impact of Intratumoral EpCAM-Positive Cancer Stem Cell Heterogeneity in Patients with Hepatocellular Carcinoma

Krause¹,

Felden²,

Casar³

et al. 2020

Preprint

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Backgrounds & Aims: Intratumoural heterogeneity of hepatocellular carcinoma (HCC) is of increasing translational interest. Dismal prognosis is frequently linked to HCC harbouring cancer stem cell (CSC)-features, represented by EpCAM-expression. However, to what extent intratumoural distribution of CSC-features impacts on recurrence after curative resection remains unknown. Hence, we aimed to investigate the spatial heterogeneity of CSC-features and its impact on clinical outcome, identifying high-risk patients amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients, who received liver resection between 2011 and 2017. Tumour specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: negative (E-/-), heterogeneous-positive (E-/+), homogeneous-positive (E+/+). The groups were further analysed with respect to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 341 tumour spots from 75 patients (77% male, median age 66 years, liver cirrhosis/fibrosis 74.6%). Risk factors were alcohol abuse in 23.9%, NASH 16.3%, HBV 14.1%, HCV 17.4% and others 28.3%, representing a typical Western cohort. E+/+ patients experienced a significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.017; RFS 5 vs. 14 vs. 18 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.024).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present. Only homogeneously positive EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. Similar to colorectal cancer, high or low risk features for recurrence could be decisive for adjuvant treatment.

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“…Interferon (IFN)-γ-induced IDO production has been demonstrated to be involved in the downstream activation of IFN-γ receptors including signal transducer and activator of transcription (STAT) proteins and the phosphatidylinositol 3-kinase (PI3K) pathway (7). B7-homolog (H)1, also referred to as CD274 or programmed death ligand 1 (PD-L1), is present in various tissues and acts as an inhibitory co-stimulatory surface molecule during immune responses, and functions through cell-to-cell contact (8,9). Although B7-H1 is constitutively expressed in naïve MSCs, IFN-γ induces significant upregulation of B7-H1 in these cells (10).…”

Section: B7-h1-mediated Immunosuppressive Properties In Human Mesenchmentioning

confidence: 99%

B7‑H1‑mediated immunosuppressive properties in human mesenchymal stem cells are mediated by STAT‑1 and not PI3K/Akt signaling

et al. 2018

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Mesenchymal stem cells (MSCs), derived from either bone marrow (BM) or Wharton's jelly (WJ), inhibit the proliferation of activated T cells, and interferon (IFN)‑γ serves an important role in this process. This process is B7‑homolog (H)1‑dependent during cell contact inhibition. However, the signaling pathway involved in B7‑H1 expression in MSCs remains largely undefined. The present study demonstrated activation of B7‑H1 by engaging signal transducer and activator of transcription (STAT)‑1 signaling in MSCs. Human BM‑ and WJ‑MSCs were isolated and cultured. The immunosuppressive effect of BM‑ and WJ‑MSCs on phytohemagglutinin (PHA)‑induced T cell proliferation was compared using direct and indirect co‑culture systems. B7‑H1 expression on BM‑ and WJ‑MSCs was detected by flow cytometry. Small interfering (si)RNA was used to knock down the expression of STAT‑1. The inhibitory effect of MSCs on T lymphocytes was observed using PHA‑induced T cell proliferation assays. IFN‑γ‑induced B7‑H1 expression on human BM‑ and WJ‑MSCs increased in a time‑dependent manner. Furthermore, the inhibitory effect of MSCs on T cell proliferation was be restored when an anti‑B7‑H1 monoclonal antibody was used. When STAT‑1 signaling was inhibited by siRNA, B7‑H1 expression on IFN‑γ‑treated MSCs decreased and T cell proliferation was restored; however, the expression of B7‑H1 did not alter upon treatment with a phosphatidylinositol‑3‑kinase (PI3K) inhibitor (LY294002). These results demonstrated that the IFN‑γ‑induced immunosuppressive properties of B7‑H1 in human BM‑ and WJ‑MSCs were mediated by STAT‑1 signaling, and not by PI3K/RAC‑α serine/threonine‑protein kinase signaling. Understanding the intracellular mechanisms underlying IFN‑γ‑induced expression of B7‑H1 in MSCs may ultimately lead to an improved understanding of MSCs and provide insight into their use as cell therapy agents.

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Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions

Cited by 45 publications

References 38 publications

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

Clinical Impact of Intratumoral EpCAM-Positive Cancer Stem Cell Heterogeneity in Patients with Hepatocellular Carcinoma

B7‑H1‑mediated immunosuppressive properties in human mesenchymal stem cells are mediated by STAT‑1 and not PI3K/Akt signaling

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