Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells

Stephen-Victor, Emmanuel; Karnam, Anupama; Fontaine, Thierry; Beauvais, Anne; Das, Mrinmoy; Hegde, Pushpa; Prakhar, Praveen; Holla, Sahana; Balaji, Kithiganahalli Narayanaswamy; Kaveri, Srini V.; Latgé, Jean‐Paul; Aimanianda, Vishukumar; Bayry, Jagadeesh

doi:10.1093/infdis/jix469

Cited by 69 publications

(67 citation statements)

References 47 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%

“…36 In addition, PD-L1 expression on DCs is critical for Treg cell induction. [37][38][39] Concurrently, in the present study, detection of cell surface PD-L1 protein via flow cytometry revealed a significant increase in the BMDC population upon CpG ODN stimulation (p = 0.0128) and LPS stimulation (p = 0.0001), moreover, PD-L1 was also significantly upregulated upon treatment with neurosphere lysate (p = 0.0244, Fig. 4e).…”

Section: Pd-1 and Pd-l1 Were Upregulated After Stdenvant Administrationsupporting

confidence: 79%

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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%

Section: Pd-1 and Pd-l1 Were Upregulated After Stdenvant Administrationsupporting

confidence: 79%

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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“…Of note, lentiviral transduction and LPS activation associated expression of secreted factors and cell surface molecules by ligand overexpressing DCs could contribute to modulation of T cell properties differently than that by APC subsets that naturally express elevated levels of these ligands. This is evident from our observation, in contrary to previous reports21,[49][50][51][52][53][54] , PD-L1 overexpressing engineered DCs do not induce an increase in Foxp3+ T cells, but these DCs suppress both Th1 and Th17 (IFNγ and IL17) responses. Nevertheless, the overall impact of engineered mono-and multi-ligand DCs on T cell function, as anticipated with enhanced engagement of T cell repressor receptors, is hyporesponsiveness/tolerance.…”

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confidence: 99%

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

Gudi

Karumuthil‐Melethil

Pérez

et al. 2019

Preprint

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Inhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production.Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.

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“…However, a previous study demonstrated that fungal proteases from A. oryzae induce the production of tolerogenic dendritic cells [15]. Moreover, Stephen-Victor et al reported that α-(1,3)-glucan polysaccharide from A. fumigatus stimulated the polarization of Tregs by inducing PD-L1 expression in human dendritic cells [24]. These data suggest that the metabolites of A. Luchuensis or components of Cha-Koji might cause an increase in the production of Tregs.…”

Section: Cha-koji Changes the Microbial Profile Of Mice But Does Not mentioning

confidence: 96%

Cha-Koji, comprising green tea leaves fermented withAspergillus luchuensis var kawachii kitahara, increases regulatory T cell production in mice and humans

Yamamoto

Suzuki

Yonezu

et al. 2018

Bioscience, Biotechnology, and Biochemistry

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Green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara (Cha-Koji) are a health food containing live A. luchuensis. In this study, we examined the effects of Cha-Koji on the immune system and the enteric environment. First, we designed a clinical trial; after ingesting Cha-Koji daily for 28 days, blood parameters and the fecal composition of the participants were analyzed. Similarly, mice were administered (oral administration) with Cha-Koji suspension or its vehicle for 14 days. Thereafter, both humans and mice were examined by analyzing their immune cell phenotypes and intestinal microbiota. Regulatory T cell (Treg) numbers were significantly increased after administering Cha-Koji. An increase of Clostridium subcluster XIVa, that were known to be rich in butyrate-producing bacterium, was observed in human feces, but not in mice. These results suggest that Cha-Koji has the ability to increase Treg production in both humans and mice, irrespective of the presence of enteric butyrate.

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Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells

Abstract: PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections.

Cited by 69 publications

References 47 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

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

Cha-Koji, comprising green tea leaves fermented withAspergillus luchuensis var kawachii kitahara, increases regulatory T cell production in mice and humans

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