TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

Wu, Meng; Chen, Xian; Lou, Jianfang; Zhang, Shuping; Zhang, Xiaojie; Huang, Lei; Sun, Ruihong; Huang, Peijun; Wang, Fang; Pan, Shiyang

doi:10.18632/oncotarget.10003

Cited by 43 publications

(37 citation statements)

References 35 publications

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“…Additionally, TGF-β1 levels were positively correlated with the percentage of CD8 + Treg cells in OC. 9 Consistent with previous reports, 10 we also confirmed that high expression TGF-β1 at least partially contributed to the suppressive function of in vitroinduced CD8 + Treg cells. Compared with CD8 + T cells cultured alone, CD8 + T cells cocultured with SKOV3 cells exhibited marked activation of p38 mitogen-activated protein kinase (MAPK), which could be inhibited by a TGF-β1-neutralizing antibody.…”

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confidence: 92%

Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

Zhang

Wang

2018

Cell Mol Immunol

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supporting

confidence: 92%

Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

Zhang

Wang

2018

Cell Mol Immunol

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“…Also, several research teams have demonstrated that in spite of the fact that the population of CD8 Tregs is much less numerous in the peripheral circulation than CD4 Tregs, in in vitro assays they are nevertheless able to suppress T-cell proliferation (as effectively as, or even better than, CD4 Tregs), acting through the release of TGFβ or via other mechanisms [ 25 , 35 , 36 ]. Given that in experimental settings CD8 + T cells were shown to convert to suppressor CD8 Tregs under the influence of the tumor cell microenvironment [ 35 , 37 ], it can be assumed that expansion of CD8 Tregs observed in systemic circulation of cervical cancer patients at a pre-metastatic stage might reflect important local level changes in their quantities, that provide a foothold for further tumor dissemination. This assumption was underpinned by Battaglia and co-authors [ 10 ] and Heeren and co-authors [ 11 ], who showed that CD8 + FoxP3 + Т cells were more frequent in metastatic tumor-draining lymph nodes in early-stage cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

Kurmyshkina

Ковчур

Schegoleva

et al. 2017

Infect Agents Cancer

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BackgroundProcesses and mechanisms responsible for systemic immune suppression in early-stage cervical cancer remain substantially underinvestigated. In this work, we focused on studying the frequencies of circulating regulatory T (CD4 and CD8 Tregs) and NK (NKregs) cells in parallel with assessment of apoptotic markers expression in T cells from patients with preinvasive and microinvasive cervical cancer, with the aim to determine whether up-regulation of apoptosis-associated markers in Т lymphocytes accompanies cervical cancer development and correlates with the change in percentages of regulatory cell populations at systemic level during the initial stages of invasive cervical cancer progression.MethodsFourty two women with histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3, including carcinoma in situ) or cervical cancer (stage IA) and 30 healthy women (control) were enrolled in the study. Peripheral blood samples were taken immediately before surgery or any treatment and immediately subjected to multicolor flow cytometry.ResultsAnalysis of a combination of CD4/CD8, CD25, CD127, and FoxP3 markers revealed a statistically significant increase in the frequencies of Tregs within both the CD4 and CD8 subsets of circulating lymphocytes in patients with CIN3 and stage IA cancer. In contrast, lower numbers of NKregs (defined as CD16dim/negCD56bright subpopulation) and increased CD56dim/CD56bright NK ratio were found in patients compared to controls, with the percentage of CD16brightCD56dim cells (major subtype of circulating NKs) showing no difference. Patients also exhibited an increased expression of CD95 in total peripheral blood T lymphocytes, along with increased level of Annexin V binding to CD95-positive cells, suggesting higher susceptibility of T cells to apoptosis and potential involvement of CD95-dependent pathway in early-stage cervical cancer. Differential analysis of CD4 and CD8 T cells revealed different trends in the change of CD95 expression, confirming that this change likely has different functional significance for these two subsets. A search for correlations between the phenotypic parameters analyzed in this study was performed to demonstrate that women with early neoplastic lesions of the cervix, such as carcinoma in situ and microinvasive carcinoma, displayed a coordinated increase in expression of Treg markers in circulating lymphocytes, along with more pronounced cross-relationships between Treg numbers, CD95 expression on T cells, and apoptosis, compared to the control group.ConclusionsThe results of this study suggest that a diversity of immune regulatory mechanisms that provide support for initial stages of invasive growth in cervical cancer patients includes systemic changes in the ratios between the principal regulatory and effector lymphocyte populations both within adaptive and innate immunity.

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“…T reg cells are CD4+CD25+ (as well as CD8+ [89,90] ) T cells that express the master T reg transcription factor forkhead box P3 (FOXP3) [91,92] . CD4+ T reg cells phenotypically diverge into two main subsets: CD4+CD45RA+FOXP3 low naïve cells with weakly suppressive functions and CD4+CD45RA-FOXP3 high effector cells with strongly suppressive functions [93] .…”

Section: Immunosuppressive Cell Subsetsmentioning

confidence: 99%

Cell-mediated immune resistance in cancer

Wang¹,

Hays²,

Rama³

et al. 2019

CDR

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The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.

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TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

Cited by 43 publications

References 35 publications

Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression

Cell-mediated immune resistance in cancer

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