What Are the Molecules Involved in Regulatory T-Cells Induction by Dendritic Cells in Cancer?

Ramos, Rodrigo Nalio; Moraes, Cristiano Jacob de; Zelante, Bruna Barbosa; Barbuto, José Alexandre Marzagão

doi:10.1155/2013/806025

Cited by 28 publications

(26 citation statements)

References 101 publications

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“…In addition, the effects of DCs on Treg cell induction and expansion appear to be dependent on PD‐L1, concurrent with the present results, wherein CpG ODN and neurosphere lysate stimulation drastically upregulated PD‐L1 on DCs, and after the combinatorial administration of anti‐PD‐L1 mAb and STDENVANT, the percentage of Foxp3 + CD4 + Treg cells decreased (Fig. c ).…”

Section: Discussionsupporting

confidence: 90%

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

Zhu

Zhang

et al. 2019

Intl Journal of Cancer

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Owing to the limited therapeutic efficacy of glioma vaccines, new strategies are required to improve cancer vaccines. Our study aimed to assess the therapeutic efficacy of a glioma vaccine called STDENVANT. This vaccine, comprising glioma stem‐like cell (GSC) lysate, dendritic cells (DCs), and Toll‐like receptor (TLR) 9 agonist CpG motif‐containing oligodeoxynucleotides (CpG ODNs), was assessed using a GL261‐C57BL/6 orthotopic mouse model of glioma. STDENVANT markedly improved survival and tumor regression by enhancing anti‐tumor immune function. Moreover, STDENVANT upregulated programmed death 1 (PD‐1) and its ligand PD‐L1 on effector T cells, DCs, and glioma tissues, resulting in the accumulation of regulatory T (Treg) cells in the brain and lymph nodes. Combinatorial administration of anti‐PD‐L1 antibody and STDENVANT conferred a greater survival advantage and decreased the Treg cell population in the brain. The present results indicate that PD‐L1 blockade can promote tumor regression via STDENVANT in a mouse model of glioma, and combinatorial administration of anti‐PD‐L1 antibody and STDENVANT increases the therapeutic anti‐tumor efficacy of treatment.

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Section: Discussionsupporting

confidence: 90%

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

Zhu

Zhang

et al. 2019

Intl Journal of Cancer

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“…Indeed, our data demonstrated that Inhα -/- mBMDCs induced poor allogeneic T cell responses, possibly as a consequence of lower levels of MHCII and CD86 expression and increased PD-L1 expression. In this context, PD-L1 has been shown to down regulate T cell receptor (TCR) signaling by recruiting SHP-2 [36] and consequently, promotes T cell anergy and Treg induction [37,38]. Whether the impaired maturation of Inhα -/- BMDCs has an impact on T cell polarization and Treg induction remains unclear and is currently being investigated.…”

Section: Discussionmentioning

confidence: 99%

A Key Role for Inhibins in Dendritic Cell Maturation and Function

et al. 2016

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Inhibins are members of the TGFβ superfamily, which regulate many cellular processes including differentiation, proliferation, survival and apoptosis. Although initially described as hormones regulating the hypothalamus-pituitary-gonadal axis, based on their ability to antagonize Activins, our group has recently reported that they play a role in thymocyte differentiation and survival, as well as in thymic stromal cell maturation and nTreg generation. Here, we used Inhibin knock out mice (Inhα-/-) to investigate the role of Inhibins in peripheral dendritic cell maturation and function. We first demonstrated that LPS treated Inhα+/+ bone marrow derived dendritic cells (BMDC) were capable to produce significant levels of Inhibin A. Interestingly, Inhα-/- BMDC showed reduced MHCII and CD86 upregulation and increased PD-L1 expression in response to LPS compared to Inhα+/+, which correlated with reduced ability to induce proliferation of allogeneic T cells. The “semi-mature” phenotype displayed by Inhα-/- mBMDC correlated with increased levels of IL-10 and slightly decreased IL-6 production after LPS stimulation. In addition, Inhα-/- mBMDC showed impaired migration towards CCL19 and CCL21, assessed by in vitro chemotaxis and in vivo competitive homing experiments, despite their normal CCR7 expression. Furthermore, in vivo LPS-induced DC maturation was also diminished in Inhα-/- mice, specially within the LC (CD207+ CD11b+ CD103-) subpopulation. Finally, analysis of delayed type hypersensitivity responses in Inhα-/- mice, showed reduced ear swelling as a result of reduced cellular infiltration in the skin, correlating with impaired homing of CD207+ DCs to the draining lymph nodes. In summary, our data demonstrate for the first time that Inhibins play a key role in peripheral DC maturation and function, regulating the balance between immunity and tolerance.

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“…38 Involved in the negative regulation of adaptive responses, 39 PD-1/PD-L1 pathway was first studied. The results indicated that the inhibition of DC maturation, the release of a tolerogenic cytokine profile (IL-12 low IL-10 high ) and the induction of Treg cells by DC committed by genital SCC cell lines could be partially mediated by RANKL.…”

Section: Discussionmentioning

confidence: 99%

Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion

et al. 2015

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The progression of genital human papillomavirus (HPV) infections into preneoplastic lesions suggests that infected/malignant cells are not adequately recognized by the immune system. In this study, we demonstrated that cervical/vulvar cancer cells secrete factor(s) that affect both the maturation and function of dendritic cells (DC) leading to a tolerogenic profile. Indeed, DC cocultured with cancer cell lines display both a partially mature phenotype after lipopolysaccharide (LPS) maturation and an altered secretory profile (IL-10high and IL-12p70low). In addition, tumor-converted DC acquire the ability to alter T-cell proliferation and to induce FoxP3+ suppressive T cells from naive CD4+ T cells. Among the immunosuppressive factors implicated in DC alterations in genital (pre)neoplastic microenvironment, we identified receptor activator of nuclear factor kappa-B ligand (RANKL), a TNF family member, as a potential candidate. For the first time, we showed that RANKL expression strongly increases during cervical progression. We also confirmed that RANKL is directly secreted by cancer cells and this expression is not related to HPV viral oncoprotein induction. Interestingly, the addition of osteoprotegerin (OPG) in coculture experiments reduces significantly the inhibition of DC maturation, the release of a tolerogenic cytokine profile (IL-12low IL-10high) and the induction of regulatory T (Treg) cells. Our findings suggest that the use of inhibitory molecules directed against RANKL in cervical/vulvar (pre)neoplastic lesions might prevent alterations of DC functionality and represent an attractive strategy to overcome immune tolerance in such cancers.

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What Are the Molecules Involved in Regulatory T-Cells Induction by Dendritic Cells in Cancer?

Cited by 28 publications

References 101 publications

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

A Key Role for Inhibins in Dendritic Cell Maturation and Function

Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion

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