scholarly journals Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

2021 ◽  
Author(s):  
Shasha Liu ◽  
Chaoqi Zhang ◽  
Boqiao Wang ◽  
Huanyu Zhang ◽  
Guohui Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Growth ◽  
Xenograft Model ◽  
Malignant Growth ◽  
Cancer Stemness ◽  
The Core ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Tumorigenic Potential

AbstractGlioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB–IL6–STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

2020 ◽  
Author(s):  
Shasha Liu ◽  
Chaoqi Zhang ◽  
Boqiao Wang ◽  
Huanyu Zhang ◽  
Congcong Li ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Noncancerous Tissue ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Tumorigenic Potential ◽  
Sphere Formation

Abstract Background: Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and the tumor microenvironment (TME). The aim of this study was to examine how regulatory T cells (Tregs) increase the stemness and tumorigenic potential of glioma cells.Methods: Tumor and peripheral blood samples were collected during surgery from 86 patients with glioma, and 75 samples of adjacent noncancerous tissue were collected, and Regulatory T cells (Tregs) were extracted from blood. Cytological and histochemical analyses were conducted to examine the mechanisms of Treg action on cancer cells. A mouse glioma model was used.Results: Intense infiltration by Tregs facilitated the qualities of GSCs through TGF-β secretion, which helped to coordinate tumor growth. Mechanistic investigations indicated that TGF-b acted on cancer cells to induce expression of the core cancer stem cell-related genes ( CD133, SOX2, NESTIN, MUSASHI1, and ALDH1A ) and to induce sphere formation via the NF-κB–IL6–STAT3 signaling pathway, resulting in increased cancer stemness and tumorigenic potential. Tregs promoted glioma tumor growth, and this effect was abrogated by blockade of the IL6 receptor by tocilizumab, which also demonstrated some therapeutic efficacy in a xenograft model. Expression levels of CD133, IL6 and TGF-β were found to serve as prognostic markers for glioma.Conclusions: Our findings reveal a new immune-associated mechanism underlying Treg-induced GSCs. Efforts to target this network may provide an effective strategy for treating glioma.

scholarly journals Regulatory T cells induce polarization of pro-repair macrophages by secreting sFGL2 into the endometriotic milieu

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Xin-Xin Hou ◽  
Xiao-Qiu Wang ◽  
Wen-Jie Zhou ◽  
Da-Jin Li
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathway ◽  
Peritoneal Fluid ◽  
Macrophage Polarization ◽  
Induce Polarization ◽  
Highly Active ◽  
Stat3 Signaling ◽  
Macrophages Polarization ◽  
Stat3 Signaling Pathway

AbstractAn increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Here, we show that the level of Tregs-derived soluble fibrinogen-like protein 2 (sFGL2) increases in the peritoneal fluid of women with endometriosis. Higher expression of FGL2 and its receptor CD32B is observed in eutopic endometrium and ectopic tissues. The production of sFGL2 in Tregs may be enhanced by several cytokines. sFGL2 selectively induces pro-repair macrophage polarization mainly through the activation of the SHP2-ERK1/2-STAT3 signaling pathway, and the suppression of the NF-κB signaling pathway. Furthermore, sFGL2 induces a much higher level of metallothionein (MT) expression that in turn facilitates pro-repair macrophages polarization. sFGL2-induced pro-repair macrophages promote Th2 and Tregs differentiation, creating a positive feedback loop. These findings suggest that sFGL2 secreted by Tregs skews macrophages toward a pro-repair phenotype via SHP2-ERK1/2-STAT3 signaling pathway, which is involved in the progression of endometriosis.

scholarly journals Robust and cost effective expansion of human regulatory T cells highly functional in a xenograft model of graft-versus-host disease

Haematologica ◽  
2012 ◽  
Vol 98 (4) ◽  
pp. 533-537 ◽  
Author(s):  
R. Chakraborty ◽  
A. Mahendravada ◽  
S. K. Perna ◽  
C. M. Rooney ◽  
H. E. Heslop ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Xenograft Model ◽  
Cost Effective ◽  
Host Disease ◽  
Graft Versus Host ◽  
Effective Expansion

scholarly journals Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yanfang Liang ◽  
Qianqian Chen ◽  
Wenjing Du ◽  
Can Chen ◽  
Feifei Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
T Lymphocyte ◽  
Epstein Barr Virus ◽  
Cytotoxic T Lymphocyte ◽  
Reciprocal Regulation ◽  
Barr Virus ◽  
Cell Responses ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Epstein Barr

Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structural subunit and can form a heterodimer with IL-27p28 and IL-12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-γproduction, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC.

Regulatory T cells mediate resistance to radiotherapy in head and neck squamous cell carcinoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 70-70 ◽  
Author(s):  
Ayman Oweida ◽  
Laurel Darragh ◽  
Shilpa Bhatia ◽  
David Raben ◽  
Lynn Heasley ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Tumor Growth ◽  
Head And Neck ◽  
Critical Role ◽  
Growth Delay ◽  
Functional Changes ◽  
Treg Depletion

70 Background: Head and neck tumors are highly enriched in regulatory T cells which dampen the response to radiotherapy by creating an immune-inhibitory microenvironment. We explored mechanisms of Treg infiltration and assessed their modulation by RT in murine models of HNSCC. Methods: Mechanisms of Treg infiltration were investigated in murine HNSCC tumors using whole genome sequencing and flow cytometry. Mice were treated with anti-CTLA-4, anti-CD-25 and/or anti-PD-L1 alone and in combination with RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T cell populations. Multiplex ELISA was performed for assessment of cytokines. RNA Sequencing was performed to interrogate mechanisms of response and resistance to treatment. Results: Treatment with anti-CD-25 concurrently with RT led to significant tumor growth delay, enhanced T cell cytotoxicity, decreased Tregs and improved survival. In contrast CTLA-4 blockade did not affect tumor growth or survival. Treg depletion induced an influx of CD8 and CD4 T cells when combined with RT. In addition, Treg depletion in combination with RT transformed myeloid populations decreasing M2 macrophages and MDSCs and increasing M1 macrophages. Mechanistically, tumors secrete CCL20, a potent Treg chemoattractant responsible for creating a highly immunuosuppressive tumor microenvironment and potentially responsible for treatment resistance. Conclusions: These data reveal a critical role for regulatory T cells in mediating resistance to RT. Targeted depletion of Tregs represents an important mechanism of sensitizing tumors to RT. Our data support the design of clinical trials integrating targeted Treg inhibitors in the standard of care for cancer patients receiving RT.

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