Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function

Ribechini, Eliana; Hutchinson, James A.; Hergovits, Sabine; Heuer, Marion; Lucas, Jörg; Schleicher, Ulrike; Garrote, Ana-Laura Jordán; Potter, Sarah; Riquelme, Paloma; Brackmann, Heike; Müller, Nora; Raifer, Hartmann; Berberich, Ingolf; Huber, Magdalena; Beilhack, Andreas; Lohoff, Michael; Bogdan, Christian; Eyrich, Matthias; Hermanns, Heike M.; Geissler, Edward K.; Lutz, Manfred B.

doi:10.1182/bloodadvances.2017006858

Cited by 77 publications

(87 citation statements)

References 56 publications

(69 reference statements)

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“…This indicates that monocyte licensing for suppression had occurred in the spleen by the CFA/CFA treatment, but no activation from L-Mono into M-MDSCs had occurred yet. These results are compatible to what we found before in vitro (21,22). Both granulocytic and monocytic cells infiltrated the white pulp T cell areas, but only CD11b + CD115 + monocytic cells were counterstained as iNOS + .…”

Section: Discussionsupporting

confidence: 93%

“…The data obtained here follow the same 2-step rules for licensing and activation of MDSCs as described before (21,22). As a critical first step, the conversion of classical Ly6C hi monocytes into L-Mono was identified as a prerequisite for the acquisition of M-MDSC suppressor function.…”

Section: Discussionsupporting

confidence: 67%

“…Again, in vitro evidence suggests that the late developmental switch from differentiated human CD14 + monocytes into either macrophages or DCs is directed by epigenetic changes (40). We found previously that in GM-CSF differentiated BM-MD-SC cultures, transcriptional and translational changes occur that are prerequisite for their development into M-MDSCs (21). Thus, it is tempting to speculate that, in M. tuberculosis-induced M-MDSC generation, epigenetic changes also can occur at a differentiated monocyte stage.…”

Section: Discussionmentioning

confidence: 83%

“…As a critical first step, the conversion of classical Ly6C hi monocytes into L-Mono was identified as a prerequisite for the acquisition of M-MDSC suppressor function. In our system, GM-CSF-mediated monocyte licensing was identified as a critical component for subsequent M-MDSC generation (21). GM-CSF is a generally accepted inducer of MDSCs (2).…”

Section: Discussionmentioning

confidence: 92%

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Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

Ribechini¹,

Eckert²,

Beilhack³

et al. 2019

JCI Insight

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models of live Mycobacterium tuberculosis infection (11). Whether vaccines containing killed M. tuberculosis would also induce MDSCs remains unclear.Among the carrier substances for antitumor or antipathogen vaccines, incomplete Freund's adjuvant (IFA), used under the name Montanide ISA-51 VG, is a suitable and widely distributed mineral oil-based adjuvant for human clinical studies with good antigen responses but also some adverse effects (12,13). Another preparation, CFA, was developed in 1942 and since then has been widely used as a vaccine adjuvant in experimental animals (14). Since CFA is composed of IFA containing heat-killed and dried M. tuberculosis, it can be considered as an M. tuberculosis vaccine. Notably, unclear tolerogenic effects had been observed after CFA vaccination in animals (14). On the one hand, CFA is a critical component for the induction of autoimmunity in models of experimental autoimmune encephalomyelitis (15, 16); on the other hand, injection of CFA could also prevent autoimmunity, such as the onset of type I diabetes in NOD mice (17) and ameliorated Parkinson's disease in rats (18). While the pathogen-induced adjuvant effects can be explained by mycobacterial triggering of TLR2 and TLR4, the tolerogenic mechanisms of CFA are not understood. The possible suppressive effects, besides their immunostimulatory function by IFA and other adjuvants in tumor vaccination studies, have been reviewed before (13). CFA-based tumor vaccines could induce suppressive CD11b + immune cells (7,19), while in an alum-based vaccine, B cell immune responses were boostered by CD11b + cells (19). However, these questions remain unclear: whether M. tuberculosis or IFA/Montanide will be able to induce MDSCs, which MDSC subsets will become activated, and what are the major target cells of their suppression in vivo.Previously, we described a simple and reliable protocol to generate murine MDSCs in vitro from murine BM precursor cells with . The generation of such human or murine M-MDSCs in vitro can be performed by following a 2-step protocol that, first, converts classical monocytes (Ly6C hi or CD14 + ) into monocytes "licensed" for suppression (L-Mono) that also can be considered as resting M-MDSCs and, second, converts L-Mono into activated M-MDSCs that release the suppressor molecules NO in the murine and IDO in the human system (21). This in vitro differentiation model exemplifies the 2 steps of signaling for M-MDSC induction that are relevant also in vivo (1). While the combination of LPS and IFN-γ for the second step of MDSC activation constituted one of the strongest signals (22), cocktails of proinflammatory cytokines were also effective (21). While the infiltration of MDSCs at vaccination sites and lymph nodes has been observed before using Mycobacterium bovis BCG, only local T cell responses seemed to be affected in these organs (23).The targets of MDSC-mediated suppression were mainly identified as macrophages, NK cells, and CD4 + or CD8 + T cells that were tested for their phagocytic activity, proli...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 92%

See 2 more Smart Citations

Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

Ribechini¹,

Eckert²,

Beilhack³

et al. 2019

JCI Insight

Self Cite

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“…1). In contrast to pathways associated with potential proinflammatory functions of GM-CSF, a time-and dose-dependent licensing process by GM-CSF in mouse and human monocytes in vitro has been described that disables their inflammatory functions and promotes their conversion into suppressor cells (Ribechini et al, 2017): this two-step licensing requires activation of the AKT/mTOR/mTORC1 signaling cascade by GM-CSF, followed by signaling through the IFNγR/IRF-1 pathway.…”

Section: Introductionmentioning

confidence: 99%

GM-CSF in inflammation

Hamilton

2019

Journal of Experimental Medicine

201

189

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Granulocyte–macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.

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G‐CSF/GM‐CSF‐induced hematopoietic dysregulation in the progression of solid tumors

Liu

Hoffman

et al. 2022

FEBS Open Bio

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There are two types of abnormal hematopoiesis in solid tumor occurrence and treatment: pathological hematopoiesis, and myelosuppression induced by radiotherapy and chemotherapy. In this review we primarily focus on the abnormal pathological hematopoietic differentiation in cancer induced by tumor‐released granulocyte colony‐stimulating factor (G‐CSF) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). As key factors in hematopoietic development, G‐CSF/GM‐CSF are well‐known facilitators of myelopoiesis and mobilization of hematopoietic stem cells (HSCs). In addition, these two cytokines can also promote or inhibit tumors, dependent on tumor type. In multiple cancer types, hematopoiesis is greatly enhanced and abnormal lineage differentiation is induced by these two cytokines. Here, dysregulated hematopoiesis induced by G‐CSF/GM‐CSF in solid tumors and its mechanism are summarized, and the prognostic value of G‐CSF/GM‐CSF‐associated dysregulated hematopoiesis for tumor metastasis is also briefly highlighted.

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Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function

Abstract: Key Points Novel GM-CSF signaling pathways through IFN-γR/IRF-1 and AKT/mTOR provide monocyte licensing for suppressor function. Only licensed but not fresh Ly-6Chigh murine or human CD14+ monocytes secrete nitric oxide or IDO for T-cell suppression.

Cited by 77 publications

References 56 publications

Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

GM-CSF in inflammation

G‐CSF/GM‐CSF‐induced hematopoietic dysregulation in the progression of solid tumors

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