Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Gargaro, Marco; Scalisi, Giulia; Manni, Giorgia; Briseño, Carlos G.; Bagadia, Prachi; Durai, Vivek; Theisen, Derek J.; Kim, Sun Kyung; Castelli, Marilena; Xu, Chenling; Hörste, Gerd Meyer zu; Servillo, Giuseppe; Fazia, Maria Agnese Della; Mencarelli, Giulia; Ricciuti, Doriana; Padiglioni, Eleonora; Giacchè, Nicola; Colliva, Carolina; Pellicciari, Roberto; Calvitti, Mario; Zelante, Teresa; Fuchs, Dietmar; Orabona, Ciriana; Boon, Louis; Bessede, Alban; Colonna, Marco; Puccetti, Paolo; Murphy, Theresa L.; Murphy, Kenneth M.; Fallarino, Francesca

doi:10.1016/j.immuni.2022.05.013

Cited by 60 publications

(43 citation statements)

References 87 publications

(119 reference statements)

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“…Both cDC and pDC may display this property. IDO1 is expressed in mature cDC1 but not in cDC2, but IDO1 competent cDC1 can induce regulatory cDC2 through tryptophan metabolism ( 76 ).…”

Section: Modulation Of DC Function In the Tumor Microenvironmentmentioning

confidence: 99%

Strategies to overcome DC dysregulation in the tumor microenvironment

2022

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Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.

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“…Both cDC and pDC may display this property. IDO1 is expressed in mature cDC1 but not in cDC2, but IDO1 competent cDC1 can induce regulatory cDC2 through tryptophan metabolism ( 76 ).…”

Section: Modulation Of DC Function In the Tumor Microenvironmentmentioning

confidence: 99%

Strategies to overcome DC dysregulation in the tumor microenvironment

2022

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“…Our data support the premise of Notch-dependent cross-talk between DC2 and DC3/monocyte lineages and show that cooperativity between these lineages has the capacity to promote the pathognomonic LCH program. Notably, a similar phenomenon of communication between lineages was recently described in the field of tolerance where idoleamine 2,3-dioxygenase (IDO)-competent DC1 induce regulatory DC2 via metabolic communication ( 41 ).…”

Section: Discussionmentioning

confidence: 68%

“…A single-cell dissection of neoplastic histiocytes and their microenvironment allows clear differentiation of functions between lineages, illustrating the potential for a tissue program to be initiated and generated by cross-talk between more than one immune cell type. This phenomenon may emerge in other settings in health and disease, as recently illustrated by the example of a tolerance program induced by metabolic signaling between DC1 and DC2 ( 41 ).…”

Section: Discussionmentioning

confidence: 94%

Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology

et al. 2022

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Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.

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“…Metabolites are chemicals that do not merely take place in the metabolic reactions, but are also involved in inter-and intra-cellular communications, energy production, macromolecule synthesis, posttranslational modifications, and cell survival (51)(52)(53)(54)(55)(56). In accordance, the enzymes responsible for their production are considered central regulators of the function of cells, including immune cells (57)(58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine

Rossini

Gagaro

Scalisi

et al. 2023

Preprint

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Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.

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Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Cited by 60 publications

References 87 publications

Strategies to overcome DC dysregulation in the tumor microenvironment

Strategies to overcome DC dysregulation in the tumor microenvironment

Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology

A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine

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