TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells

Carambia, Antonella; Freund, Barbara; Schwinge, Dorothee; Heine, Markus; Laschtowitz, Alena; Huber, Samuel; Wraith, David C.; Korn, Thomas; Schramm, Christoph; Lohse, Ansgar W.; Heeren, Joerg; Herkel, Johannes

doi:10.1016/j.jhep.2014.04.027

Cited by 204 publications

(192 citation statements)

References 33 publications

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“…These tumor microenvironments of HCC, where the recruitment and retention of immunosuppressive cells take place [42] , should disturb effective immune therapies. Endothelial cells also induce Treg induction in a TGF-β-dependent manner [43] . These cells also express FasL, which plays a role in tumor invasion into the parenchyma and elimination of infiltrating CTLs [44] .…”

Section: Hepatic Stellate Cells Endothelial Cells and Cancer-associmentioning

confidence: 99%

Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication

Nishida¹,

Kudo²

2016

Oncology

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Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC.

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Section: Hepatic Stellate Cells Endothelial Cells and Cancer-associmentioning

confidence: 99%

Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication

Nishida¹,

Kudo²

2016

Oncology

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“…A sufficient quantity of Tregs is critical in keeping inflammation balance and reducing tissue injury (Li et al, 2009;Fogle et al, 2010b;Tang et al, 2014;Zhao et al, 2015;Zhang et al, 2016). Excessive activity or quantity of Tregs can promote infectious deterioration, sepsis, or tumor immune escape, whereas an insufficient amount can result in overactive inflammatory responses (Burgents et al, 2010;Fogle et al, 2010a;Carambia et al, 2014). Tregs have been shown to be differentially influenced by various resuscitation fluids after hemorrhagic shock (Murao et al, 2009;Isayama et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Immune recovery after fluid resuscitation in rats with severe hemorrhagic shock

Feng

Jiang

et al. 2017

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To investigate the effects of resuscitation with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES) on regulatory T cells (Tregs), helper T 1 (Th1)/Th2 and cytotoxic T 1 (Tc1)/Tc2 profiles in the treatment of hemorrhagic shock. Methods: Rats subjected to severe hemorrhagic shock were resuscitated for 30 min with NS (n=8), HTS (n=8), or HES (n=8); sham (n=8) and naive control (n=8) groups were used for comparison. Following fluid resuscitation, the whole shed blood was reinfused for 30 min, and the rats were observed with continuous hemodynamic monitoring for 120 min. CD4 + CD25 + Foxp3 + Treg proportions, Th1/Th2 and Tc1/Tc2 profiles in spleen were analyzed by three-color flow cytometry. Results: The proportion of CD4 + CD25 + Foxp3 + Tregs and ratios of Th1/Th2 and Tc1/Tc2 did not differ among control, sham, and HTS groups, but were significantly lower in NS and HES groups (both P<0.05 vs. sham); NS and HES levels were similar. The level of Tc1 was significantly increased in HTS (P<0.05 vs. sham), and levels of Tc2 were increased in NS, HES, and HTS groups compared to sham (all P<0.05), but did not differ from each other. Conclusions: HTS resuscitation has a greater impact on immune system recovery than NS or HES by preserving the proportion of Tregs and maintaining the balance between Th1/Th2 and Tc1/Tc2 cells in the spleen. Thus, HTS resuscitation provides potential immunomodulatory activity in the early stage after hemorrhagic shock.

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“…A comparative analysis of liver APCs concluded that LSECs are the major cell type that stimulates TGFb dependent induction of CD4 + Foxp3 + Tregs. This is possible because LSECs not only can secrete TGFb but also tether LAP/TGFb to their membrane through GARP [13 ]. Once induced by LSECs, antigen-specific Tregs can be potent suppressors of autoimmune inflammation, as evidenced by in vivo studies in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis.…”

Section: Liver Sinusoidal Endothelial Cellsmentioning

confidence: 99%