Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria

Hirako, Isabella C.; Ataide, Marco A.; Faustino, Lucas; Assis, Patrícia A.; Sorensen, Elizabeth W.; Ueta, Hisashi; Araújo, Natalia M.; Menezes, Gustavo B.; Luster, Andrew D.; Gazzinelli, Ricardo T.

doi:10.1038/ncomms13277

Cited by 51 publications

(69 citation statements)

References 69 publications

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“…Previous studies have shown that CXCL9 and CXCL10 can be secreted by multiple cell types including monocytes, endothelial cells, fibroblasts, inflammatory macrophages dendritic cells (particularly the cDC1 subtype) and tumor cells themselves (9,12,13,(66)(67)(68). In the context of cancer, previous data have suggested that tumor cells (68), CD103 þ DCs (9, 12, 69), or CD11b þ cells (67) are major sources of CXCL9/10 within the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

House

Savas

Lai

et al. 2020

Clinical Cancer Research

448

320

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Purpose: Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies. Experimental Design: The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoStringbased analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses. Results: The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8 þ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8 þ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/ 10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB. Conclusions: These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.

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Section: Discussionmentioning

confidence: 99%

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

House

Savas

Lai

et al. 2020

Clinical Cancer Research

448

320

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“…Myeloid cells that include monocytes and monocyte-derived DCs have indeed been reported to be major producers of CXCL9 and CXCL10 in the inflamed brain (27). Recent studies indicate that CCR2 + myeloid cells precede CD4 + T cell infiltration in the heart in response to TAC, and their depletion results in impaired CD4 + T cell expansion in the mLNs and subsequent recruitment to the heart (40,41). Our data, in line with these studies, demonstrate that a high percentage of CCR2 + -recruited monocytes and macrophages are indeed a source of CXCL10 and that CCR2 + macrophages also produce CXCL9.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

Ngwenyama¹,

Salvador²,

Velázquez³

et al. 2019

JCI Insight

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“…Further, Mo-DCs have been recently shown to be one of the major CXCL9/10 producers in the spleen during the development of ECM. These cells were shown to traffic to the brain in a CCR5-dependent manner, possibly also contributing to the induction of T cell trafficking to the brain during the development of ECM by acting as early sources of CXCL9 and CXCL10 (69). Here, we have shown that there exists a population of iMOs and Mo-DCs firmly adhered to the lumen of the brain postcapillary venules, which produce high levels of both CXCL9 and -10 that are, in combination with EC-produced CXCL10, activating CXCR3 on the T cells in the blood and thus contributing to T cell-EC interactions within the brain during CM.…”

Section: Discussionmentioning

confidence: 99%

CXCL10 stabilizes T cell–brain endothelial cell adhesion leading to the induction of cerebral malaria

Sorensen¹,

Lian²,

Ozga³

et al. 2018

JCI Insight

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Malaria remains one of the world's most significant human infectious diseases and cerebral malaria (CM) is its most deadly complication. CM pathogenesis remains incompletely understood, hindering the development of therapeutics to prevent this lethal complication. Elevated levels of the chemokine CXCL10 are a biomarker for CM, and CXCL10 and its receptor CXCR3 are required for experimental CM (ECM) in mice, but their role has remained unclear. Using multiphoton intravital microscopy, CXCR3 receptor- and ligand-deficient mice and bone marrow chimeric mice, we demonstrate a key role for endothelial cell-produced CXCL10 in inducing the firm adhesion of T cells and preventing their cell detachment from the brain vasculature. Using a CXCL9 and CXCL10 dual-CXCR3-ligand reporter mouse, we found that CXCL10 was strongly induced in the brain endothelium as early as 4 days after infection, while CXCL9 and CXCL10 expression was found in inflammatory monocytes and monocyte-derived DCs within the blood vasculature on day 8. The induction of both CXCL9 and CXCL10 was completely dependent on IFN-γ receptor signaling. These data demonstrate that IFN-γ-induced, endothelium-derived CXCL10 plays a critical role in mediating the T cell-endothelial cell adhesive events that initiate the inflammatory cascade that injures the endothelium and induces the development of ECM.

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Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria

Cited by 51 publications

References 69 publications

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

CXCL10 stabilizes T cell–brain endothelial cell adhesion leading to the induction of cerebral malaria

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