The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity

Laoui, Damya; Keirsse, Jiri; Morias, Yannick; Overmeire, Eva Van; Geeraerts, Xenia; Elkrim, Yvon; Kiss, Máté; Bolli, Evangelia; Lahmar, Qods; Sichien, Dorine; Serneels, Jens; Scott, Charlotte; Boon, Louis; Baetseĺier, Patrick De; Mazzone, Massimiliano; Guilliams, Martin; Ginderachter, Jo A. Van

doi:10.1038/ncomms13720

Cited by 218 publications

(274 citation statements)

References 56 publications

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“…S1D). These phenotypes are consistent with those described for CD11b + and CD11b - CD103 + conventional DC subsets in normal (40) and tumor (41, 42) tissues, and distinct from those described for F4/80 + CD24 lo CD64 + Mφ /TAM (41). Thus, we will henceforth refer to the CD11b +/- CD11c hi MHC-II hi populations as CD11b + and CD11b - DC.…”

Section: Resultssupporting

confidence: 88%

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Treg, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DC use this particular pathway to inhibit CD8 T cell-mediated tumor immunity. Phenotypically similar DC accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Treg and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection.

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Section: Resultssupporting

confidence: 88%

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

et al. 2017

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“…In some settings, however, IFN-g may switch monocyte differentiation from DCs to macrophages (38). Reports of other studies have shown that monocyte-derived tumor DCs suppress CTL proliferation (14), which was linked to their expression of iNOS and production of NO. In our study, ∼50% of DC3 express iNOS in both WT and Zbtb46-DTR bone marrow chimeras.…”

Section: Discussionmentioning

confidence: 99%

“…The success of PD-1-based immunotherapies depends on CD28 costimulation by B7-expressing tumor APCs to promote T cell expansion and prevent T cell exhaustion (45,46). Given the natural abundance of tumor DC3 in various human cancers (14), they provide an additional therapeutic target to boost antitumor immune responses. …”

Section: Discussionmentioning

confidence: 99%

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Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Diao

Tang

et al. 2018

The Journal of Immunology

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The success of adoptive CTL therapy for cancer depends on interactions between tumor-infiltrating CTLs and cancer cells as well as other cells and molecules in the tumor microenvironment. Tumor dendritic cells (DCs) comprise several subsets: CD103+CD11b− DC1 and CD11b+CD64− DC2, which originate from circulating precursors of conventional DCs, and CD11b+CD64+ DC3, which arise from monocytes. It remains controversial which of these subset(s) promotes intratumor CTL proliferation, expansion, and function. To address this issue, we used the Zbtb46-DTR–transgenic mouse model to selectively deplete DC1 and DC2 from tumors and lymphoid tissues. Wild-type and Zbtb46-DTR bone marrow chimeras were inoculated with B16 melanoma cells that express OVA and were treated with OT-1 CTLs. We found that depletion of DCs derived from precursors of conventional DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in tumor-draining lymph nodes. By contrast, intratumor CTL accumulation, proliferation, and IFN-γ expression were unaffected by their absence. We found that adoptive cell therapy increases the frequency of monocyte-derived tumor DC3, which possess the capacity to cross-present tumor Ags and induce CTL proliferation. Our findings support the specialized roles of different DC subsets in the regulation of antitumor CTL responses.

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“…73,103 In addition, the tumor microenvironment may have major impact on the production of functionally and phenotypically different DC subsets. 27,28,104,105 It will be intriguing to investigate under these inflammatory conditions whether and how epigenetic effects may help immune cells to adopt previously recognized phenotype and functions, thereby influencing overall consequence of immune responses.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of Dendritic Cell Development and Function

Tian¹,

Meng²,

Zhang³

2017

Cancer J

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The immune system is characterized by the generation of structurally and functionally heterogeneous immune cells that constitute complex innate and adaptive immunity. This heterogeneity of immune cells results from changes in the expression of genes without altering DNA sequence. To achieve this heterogeneity, immune cells orchestrate the expression and functional status of transcription factor (TF) networks, which can be broadly categorized into 3 classes: pioneer TFs that facilitate initial commitment and differentiation of hematopoietic cells, subset-specific TFs that promote the generation of selected cell lineages, and immune-signaling TFs that regulate specialized function in differentiated cells. Epigenetic mechanisms are known to be critical for organizing the TF networks, thereby controlling immune cell lineage-fate decisions, plasticity, and function. The effects of epigenetic regulators can be heritable during cell mitosis, primarily through the modification of DNA and histone methylation patterns at gene loci. By doing so, the immune system is enabled to mount a selective but robust response to stimuli, such as pathogens, tumor cells, autoantigens, or allogeneic antigens in the setting of transplantation, while preserving the immune cell reservoir necessary for protecting the host against numerous other unexpected stimuli and limit detrimental effect of systemic inflammatory reactions.

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The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity

Cited by 218 publications

References 56 publications

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Epigenetic Regulation of Dendritic Cell Development and Function

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