Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

Labidi-Galy, Sana Intidhar; Sisirak, Vanja; Méeus, Pierre; Gobert, Michael; Treilleux, Isabelle; Bajard, Agathe; Combes, Jean‐Damien; Faget, Julien; Mithieux, François; Cassignol, Alexandre; Trédan, Olivier; Durand, Isabelle; Ménétrier‐Caux, Christine; Caux, Christophe; Blay, Jean‐Yves; Ray‐Coquard, Isabelle; Bendriss‐Vermare, Nathalie

doi:10.1158/0008-5472.can-11-0367

Cited by 201 publications

(218 citation statements)

References 47 publications

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“…By contrast, the capacity of CCR-derived pDCs to produce IFNa upon CpG stimulation was partially defective (Fig. 9f), as largely documented in patients with other carcinoma types 34,40,41 . Significantly, number and function (for example, cytokine production) of the slanDC contingent was maintained even in advanced disease stages (Fig.…”

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confidence: 57%

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

et al. 2014

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Dendritic cells (DCs) initiate adaptive immune responses to cancer cells by activating naive T lymphocytes. 6-sulfo LacNAc þ DCs (slanDCs) represent a distinct population of circulating and tissue proinflammatory DCs, whose role in cancer immune surveillance is unknown. Herein, by screening a large set of clinical samples, we demonstrate accumulation of slanDCs in metastatic tumour-draining lymph nodes (M-TDLN) from carcinoma patients. Remarkably, slanDCs are absent at the primary carcinoma site, while their selective nodal recruitment follows the arrival of cancer cells to M-TDLN. slanDCs surround metastatic carcinoma deposits in close proximity to dead cells and efficiently phagocytose tumour cells. In colon carcinoma patients, the contingent of circulating slanDCs remains intact and competent in terms of IL-12p70 and tumour necrosis factor alpha production, induction of T-cell proliferation and migratory capacity to a set of chemokines produced in M-TDLN. We conclude that activated slanDCs represent previously unrecognized players of nodal immune responses to cancer cells.

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confidence: 57%

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

et al. 2014

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“…3D). In the development of active immunotherapeutic strategies, much attention has been focused on CD11b þ cDC-based vaccines that have failed to induce sufficient clinical efficacy (26), as pDCs are considered to be involved in the maintenance of antitumor tolerance (27) and to be inversely correlated with prognosis in patients with cancer (28,29 Fig. 3E and F).…”

Section: Discussionmentioning

confidence: 99%

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

Narusawa

Inoue

Sakamoto

et al. 2014

Cancer Immunology Research

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Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF-sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)-related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF-induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDCdepleted or IFNa receptor knockout (IFNAR À/À ) mice were used. Importantly, in both LLC and CT26 colon cancer-bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4 þ CD25 þ FoxP3 þ regulatory T cells in TDLNs.Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF-based cancer immunotherapy. Cancer Immunol Res; 2(6); 568-80. Ó2014 AACR.

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“…DCs are found in both murine and human tumors (1,2), and increased infiltration by activated DCs correlates with better patient survival (2,3). Conversely, impaired cytokine production by DCs is linked to cancer progression (4,5). DCs in tumors or tumor-draining lymph nodes (LNs) were shown to be loaded with tumor Ag (1,6), but were unable to prime tumor-specific CTLs (1,6,7).…”

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confidence: 99%

Increased Numbers of Monocyte-Derived Dendritic Cells during Successful Tumor Immunotherapy with Immune-Activating Agents

Kühn

Hyde

Yang

et al. 2013

The Journal of Immunology

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Local treatment with selected TLR ligands or bacteria such as bacillus Calmette–Guérin increases antitumor immune responses and delays tumor growth. It is thought that these treatments may act by activating tumor-associated dendritic cells (DCs), thereby supporting the induction of antitumor immune responses. However, common parameters of successful immune activation have not been identified. We used mouse models to compare treatments with different immune-activating agents for the ability to delay tumor growth, improve priming of tumor-specific T cells, and induce early cytokine production and DC activation. Treatment with polyinosinic-polycytidylic acid or a combination of monosodium urate crystals and Mycobacterium smegmatis was effective at delaying the growth of s.c. B16 melanomas, orthotopic 4T1 mammary carcinomas, and reducing 4T1 lung metastases. In contrast, LPS, monosodium urate crystals, or M. smegmatis alone had no activity. Effective treatments required both NK1.1+ and CD8+ cells, and resulted in increased T cell priming and the infiltration of NK cells and CD8+ T cells in tumors. Unexpectedly, both effective and ineffective treatments increased DC numbers and the expression of costimulatory molecules in the tumor-draining lymph node. However, only effective treatments induced the rapid appearance of a population of monocyte-derived DCs in the draining lymph node, early release of IL-12p70 and IFN-γ, and low IL-10 in the serum. These results suggest that the activation of existing DC subsets is not sufficient for the induction of antitumor immune responses, whereas early induction of Th1 cytokines and monocyte-derived DCs are features of successful activation of antitumor immunity.

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Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

Cited by 201 publications

References 47 publications

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

Increased Numbers of Monocyte-Derived Dendritic Cells during Successful Tumor Immunotherapy with Immune-Activating Agents

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