A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1

Sheng, Huiming; Wang, Ying; Jin, Yuqing; Zhang, Qiuyu; Zhang, Yan; Wang, Li; Shen, Baihua; Yin, Shuo; Liu, Wei; Cui, Lei; Li, Ningli

doi:10.1038/cr.2008.80

Cited by 353 publications

(285 citation statements)

References 41 publications

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“…23,31,32 This correlation was in accordance with the previous finding that IFNg, expressed by activated CD8 C T cells, can induce PD-L1 expression in the surrounding tumor cells. 33 Moreover, seven patients (Table 2) with absent or focal TILs still presented PD-L1 positivity. Thus, we hypothesized that PD-L1 expression in tumor cells can be constitutive and/or induced by TILs in PeSCC.…”

Section: Discussionmentioning

confidence: 96%

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Deng

Guo

et al. 2017

OncoImmunology

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Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumorinfiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8 C TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNg) and CD8 C gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNg stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 96%

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Deng

Guo

et al. 2017

OncoImmunology

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“…Indeed, several studies have revealed that when MSC are administered in the absence of IFN-g or other inflammatory signals, they fail to exert significant immune modulatory activity [33,35]. Thus, we conducted studies to determine whether MSC activation by IFN-g was also required for activity by canine MSC.…”

Section: Immune Mechanisms Canine Mesenchymal Stem Cells 383mentioning

confidence: 99%

“…It is now accepted that MSC generally do not exert their immune suppressive effects until they are activated to upregulate T cell suppressive pathways by proinflammatory cytokines, especially IFN-g [35,36]. Indeed, several studies have revealed that when MSC are administered in the absence of IFN-g or other inflammatory signals, they fail to exert significant immune modulatory activity [33,35].…”

Section: Immune Mechanisms Canine Mesenchymal Stem Cells 383mentioning

confidence: 99%

“…For rodent MSC, the nitric oxide (NO)-dependent immune suppressive pathways predominate [33], though other pathways including TGF-b and IL-10 have been reported [34]. It is also important to note that these immune modulatory pathways typically only become operative after the MSC have first been activated immunologically, typically by proinflammatory cytokines such as IFN-g, TNF-a, IL-1b, or IL-17, or by certain TLR (Tolllike receptor) ligands [35][36][37]. Thus, in most assays used to evaluate MSC immune suppressive pathways, activated T cells are cocultured with MSC, and in these assays the activated T cells provide the source of MSC-activating cytokines.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Programmed death ligand 1 (PD-L1) and human leukocyte antigen-G1 (HLA-G1) expression have been linked to the cell contact-dependent mechanisms [8,[19][20][21], while transforming growth factor beta (TGF-b), hepatocyte growth factor, interleukin-10 (IL-10), indoleamine 2,3-dioxygenase (IDO), nitric oxide, prostaglandin E2 (PGE 2 ), and human leukocyte antigen-G5 (HLA-G5) have been identified as secreted factors [1,5,8]. Currently, there is controversy regarding the need for direct contact between MSCs and T cells to inhibit T-cell proliferation [4,8,11,[19][20][21][22][23]. Additionally, studies of activation marker expression are also controversial.…”

Section: Introductionmentioning

confidence: 99%

Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

Castro-ManrrezaMarta

MayaniHéctor

García

et al. 2014

Stem Cells and Development

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Bone marrow-mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used in cell therapies as immune regulators for the treatment of graft-versus-host disease. We have previously characterized several biological properties of MSCs from placenta (PL) and umbilical cord blood (UCB), and compared them to those of BM-the gold standard. In the present study, we have compared MSCs from BM, UCB, and PL in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3 + T cells. Our results confirm the immunosuppressive potential of BM-MSCs, and demonstrate that MSCs from UCB and, to a lesser extent PL, also have immunosuppressive potential. In contrast to PL-MSCs, BMMSCs and UCB-MSCs significantly inhibited the proliferation of both CD4+ and CD8 + activated T cells in a cell-cell contact-dependent manner. Such a reduced proliferation in cell cocultures correlated with upregulation of programmed death ligand 1 on MSCs and cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) on T cells, and increased production of interferon-g, interleukin-10, and prostaglandin E2. Importantly, and in contrast to PL-MSCs, both BM-MSCs and UCB-MSCs favored the generation of T-cell subsets displaying a regulatory phenotype CD4 + CD25 + CTLA-4 + . Our results indicate that, besides BM-MSCs, UCB-MSCs might be a potent and reliable candidate for future therapeutic applications.

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A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1

Cited by 353 publications

References 41 publications

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

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

Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

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