Publications by authors named "Nathalie Bendriss-Vermare"

45 Publications

Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs.

Clin Transl Immunology 2020 8;9(12):e1208. Epub 2020 Dec 8.

Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.

Objectives: C-type lectin receptors (CLRs) are key receptors used by DCs to orchestrate responses to pathogens. During infections, the glycan-lectin interactions shape the virus-host interplay and viruses can subvert the function of CLRs to escape antiviral immunity. Recognition of virus/viral components and uptake by CLRs together with subsequent signalling cascades are crucial in initiating and shaping antiviral immunity, and decisive in the outcome of infection. Yet, the interaction of hepatitis B virus (HBV) with CLRs remains largely unknown. As HBV hijacks DC subsets and viral antigens harbour glycan motifs, we hypothesised that HBV may subvert DCs through CLR binding.

Methods: We investigated here the pattern of CLR expression on BDCA1 cDC2s, BDCA2 pDCs and BDCA3 cDC1s from both blood and liver of HBV-infected patients and explored the ability of HBsAg to bind DC subsets through specific CLRs.

Results: We highlighted for the first time that the CLR repertoire of circulating and intrahepatic cDC2s, cDC1s and pDCs was perturbed in patients with chronic HBV infection and that some CLR expression levels correlated with plasma HBsAg and HBV DNA levels. We also identified candidate CLR responsible for HBsAg binding to cDCs (CD367/DCIR/CLEC4A, CD32/FcɣRIIA) and pDCs (CD369/DECTIN1/CLEC7A, CD336/NKp44) and demonstrated that HBsAg inhibited DC functions in a CLR- and glycosylation-dependent manner.

Conclusion: HBV may exploit CLR pathways to hijack DC subsets and escape from immune control. Such advances bring insights into the mechanisms by which HBV subverts immunity and pave the way for developing innovative therapeutic strategies to restore an efficient immune control of the infection by manipulating the viral glycan-lectin axis.
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http://dx.doi.org/10.1002/cti2.1208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723857PMC
December 2020

BDCA1 cDC2s, BDCA2 pDCs and BDCA3 cDC1s reveal distinct pathophysiologic features and impact on clinical outcomes in melanoma patients.

Clin Transl Immunology 2020 24;9(11):e1190. Epub 2020 Nov 24.

Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble 38000 France.

Objectives: Dendritic cells play a pivotal but still enigmatic role in the control of tumor development. Composed of specialised subsets (cDC1s, cDC2s, pDCs), DCs are critical in triggering and shaping antitumor immune responses. Yet, tumors exploit plasticity of DCs to subvert their functions and escape from immune control. This challenging controversy prompted us to explore the pathophysiological role of cDCs and pDCs in melanoma, where their precise and coordinated involvement remains to be deciphered.

Methods: We investigated in melanoma patients the phenotypic and functional features of circulating and tumor-infiltrating BDCA1 cDC2s, BDCA2 pDCs and BDCA3 cDC1s and assessed their clinical impact.

Results: Principal component analyses (PCA) based on phenotypic or functional parameters of DC subsets revealed intra-group clustering, highlighting specific features of DCs in blood and tumor infiltrate of patients compared to healthy donors. DC subsets exhibited perturbed frequencies in the circulation and actively infiltrated the tumor site, while harbouring a higher activation status. Whereas cDC2s and pDCs displayed an altered functionality in response to TLR triggering, circulating and tumor-infiltrating cDC1s preserved potent competences associated with improved prognosis. Notably, the proportion of circulating cDC1s predicted the clinical outcome of melanoma patients.

Conclusion: Such understanding uncovers critical and distinct impact of each DC subset on clinical outcomes and unveils fine-tuning of interconnections between DCs in melanoma. Elucidating the mechanisms of DC subversion by tumors could help designing new therapeutic strategies exploiting the potentialities of these powerful immune players and their cross-talks, while counteracting their skewing by tumors, to achieve immune control and clinical success.
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http://dx.doi.org/10.1002/cti2.1190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684973PMC
November 2020

Inflammasome Deletion Promotes Anti-tumor NK Cell Function in an IL-1/IL-18 Independent Way in Murine Invasive Breast Cancer.

Front Oncol 2020 16;10:1683. Epub 2020 Sep 16.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Lyon, France.

Inflammasomes are molecular complexes that trigger an inflammatory response upon detection of pathogens or danger signals. Recent studies suggest that they are also involved in cancer progression. However, their roles during tumorigenesis remain poorly understood and controversial. Here, we investigated whether inflammasome activation supports mammary tumor growth. Using mouse models of invasive breast cancer, our results demonstrate that the absence of a functional inflammasome impairs tumor growth. Importantly, tumors implanted into inflammasome-deficient mice recruited significantly less neutrophils and more natural killer (NK) cells, and these latter cells displayed a more active phenotype. Interestingly, NK cell depletion abolished the anti-tumoral effect observed in inflammasome-deficient mice, although inflammasome-regulated cytokine neutralization had no effect. Thus, our work identifies a novel role for the inflammasome in supporting mammary tumor growth by attenuating NK cell recruitment and activity. These results suggest that inflammasome inhibition could be a putative target for treating invasive breast cancers.
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http://dx.doi.org/10.3389/fonc.2020.01683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526436PMC
September 2020

Durable and controlled depletion of neutrophils in mice.

Nat Commun 2020 06 2;11(1):2762. Epub 2020 Jun 2.

Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland.

Neutrophils are an essential part of the innate immune system. To study their importance, experimental studies often aim to deplete these cells, generally by injecting anti-Ly6G or anti-Gr1 antibodies. However, these approaches are only partially effective, transient or lack specificity. Here we report that neutrophils remaining after anti-Ly6G treatment are newly derived from the bone marrow, instead of depletion escapees. Mechanistically, newly generated, circulating neutrophils have lower Ly6G membrane expression, and consequently reduced targets for anti-Ly6G-mediated depletion. To overcome this limitation, we develop a double antibody-based depletion strategy that enhances neutrophil elimination by anti-Ly6G treatment. This approach achieves specific, durable and controlled reduction of neutrophils in vivo, and may be suitable for studying neutrophil function in experimental models.
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http://dx.doi.org/10.1038/s41467-020-16596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265525PMC
June 2020

IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer.

Sci Immunol 2020 04 17;5(46). Epub 2020 Apr 17.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France.

Dendritic cells play a key role in the orchestration of antitumor immune responses. The cDC1 (conventional dendritic cell 1) subset has been shown to be essential for antitumor responses and response to immunotherapy, but its precise role in humans is largely unexplored. Using a multidisciplinary approach, we demonstrate that human cDC1 play an important role in the antitumor immune response through their capacity to produce type III interferon (IFN-λ). By analyzing a large cohort of breast primary tumors and public transcriptomic datasets, we observed specific production of IFN-λ1 by cDC1. In addition, both IFN-λ1 and its receptor were associated with favorable patient outcomes. We show that IFN-III promotes a T1 microenvironment through increased production of IL-12p70, IFN-γ, and cytotoxic lymphocyte-recruiting chemokines. Last, we showed that engagement of TLR3 is a therapeutic strategy to induce IFN-III production by tumor-associated cDC1. These data provide insight into potential IFN- or cDC1-targeting antitumor therapies.
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http://dx.doi.org/10.1126/sciimmunol.aav3942DOI Listing
April 2020

CD163 tumor-associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes.

Clin Transl Immunology 2020 13;9(2):e1108. Epub 2020 Feb 13.

INSERM U1052 CNRS 5286 Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon Univ Lyon Université Claude Bernard Lyon 1 Lyon France.

Objectives: The accumulation of tumor-associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans.

Methods: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) . Additionally, we used transcriptomic analysis to evaluate BC patients' blood monocytes profiles.

Results: We observed that high intra-tumor CD163-expressing TAM density is predictive of reduced survival in BC patients. , M-CSF, TGF-β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163CD86IL-10 M2-like MΦ that strongly suppressed CD4 T-cell expansion PD-L1 and IL-10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to stimulation, being refractory to type-1 MΦ (M1-MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic-related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de-activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1-MΦ differentiation showed up-regulation of IFN-response genes and had no signs of metabolic alteration.

Conclusion: Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro-metastatic profile, resulting in the accumulation of further polarised CD163 TAMs resembling type-2 MΦ (M2-MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions.
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http://dx.doi.org/10.1002/cti2.1108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017151PMC
February 2020

Neutrophil Heterogeneity in Cancer: From Biology to Therapies.

Front Immunol 2019 20;10:2155. Epub 2019 Sep 20.

Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France.

Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2019.02155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764113PMC
October 2020

Human Tumor-Infiltrating Dendritic Cells: From in Situ Visualization to High-Dimensional Analyses.

Cancers (Basel) 2019 Jul 30;11(8). Epub 2019 Jul 30.

Joint first author..

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers.
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http://dx.doi.org/10.3390/cancers11081082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721288PMC
July 2019

Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection.

J Hepatol 2019 12 23;71(6):1086-1098. Epub 2019 Jul 23.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France. Electronic address:

Background & Aims: Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively).

Methods: PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses.

Results: HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1β, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes.

Conclusions: Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection.

Lay Summary: Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1β, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition.
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http://dx.doi.org/10.1016/j.jhep.2019.06.032DOI Listing
December 2019

Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection.

Front Immunol 2019 4;10:112. Epub 2019 Feb 4.

Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.

Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored. One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach. We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels. We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus.
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http://dx.doi.org/10.3389/fimmu.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369167PMC
December 2019

[Immunotherapy and targeted therapy, a promising combination to fight cancer].

Med Sci (Paris) 2018 Oct 19;34(10):872-875. Epub 2018 Nov 19.

Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS 5286, centre Léon Bérard, centre de recherche en cancérologie de Lyon, Lyon, 69008, France.

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http://dx.doi.org/10.1051/medsci/2018217DOI Listing
October 2018

Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines.

J Innate Immun 2018 5;10(4):339-348. Epub 2018 Jul 5.

INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard (CLB), Lyon, France.

Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development.
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http://dx.doi.org/10.1159/000489966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757176PMC
October 2019

Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells.

Antimicrob Agents Chemother 2018 04 27;62(4). Epub 2018 Mar 27.

INSERM, U1052, CNRS, UMR_5286, Cancer Research Center of Lyon (CRCL), Lyon, France

We previously reported that Toll-like receptor 9 (TLR9)-CpG oligonucleotides could inhibit the establishment of hepatitis B virus (HBV) infections in hepatocytes. Our aim was to uncover the underlying mechanisms of this inhibition. HepaRG cells, RPMI-B lymphoblastoma cells, and primary plasmacytoid dendritic cells (pDCs) exposed to HBV and TLR9 ligands/agonists in various configurations were used. We observed an inhibition of HBV infection upon TLR9 stimulations only when agonist was applied during inoculation. This inhibition was independent of interleukin-6 (IL-6)/interferon-inducible protein 10 (IP-10) production as well as of TLR9 expression in hepatocytes. We further demonstrated an entry inhibition mechanism by showing a noncovalent binding of TLR9 agonist to HBV particles. Besides inhibiting HBV entry into hepatocytes, this biophysical interaction between HBV virions and TLR9 agonist was responsible for a reduction of alpha interferon (IFN-α) expression by pDCs. Interestingly, subviral particles composed of only HBsAg were able to genuinely inhibit the TLR9 pathway, without titrating TLR9 ligands. To conclude, our data suggest that synthetic TLR9-CpG oligonucleotides can strongly inhibit HBV entry by "coating" HBV virions and thereby preventing their interaction with cellular receptor. This titration effect of TLR9 agonist is also artifactually responsible for the inhibition of TLR9 engagement in pDCs, whereas a genuine inhibition of this innate pathway was confirmed with HBsAg subviral particles.
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http://dx.doi.org/10.1128/AAC.01741-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913918PMC
April 2018

Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.

Acta Neuropathol 2018 04 3;135(4):569-579. Epub 2018 Jan 3.

Institut NeuroMyogène, Equipe Synaptopathies et Autoanticorps (SynatAc), INSERM U1217/UMR CRS 5310, Lyon, France.

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.
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http://dx.doi.org/10.1007/s00401-017-1802-yDOI Listing
April 2018

BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells.

Nat Commun 2017 10 13;8(1):913. Epub 2017 Oct 13.

Aix Marseille Université, CNRS, INSERM, CIML, 13288, Marseille cedex 9, France.

Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1 late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3LAMP2LAMP1 endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression. BAD-LAMP-silencing enhances TLR9 retention in this compartment and consequent downstream signalling events. Conversely, sustained BAD-LAMP expression in pDCs contributes to their lack of type I interferon production after exposure to a TGF-β-positive microenvironment or isolation from human breast tumours. Hence, BAD-LAMP limits interferon expression in pDCs indirectly, by promoting TLR9 sorting to late endosome compartments at steady state and in response to immunomodulatory cues.TLR9 is highly expressed by plasmacytoid dendritic cells and detects nucleic acids, but to discriminate between host and microbial nucleic acids TLR9 is sorted into different endosomal compartments. Here the authors show that BAD-LAMP limits type 1 interferon responses by sorting TLR9 to late endosomal compartments.
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http://dx.doi.org/10.1038/s41467-017-00695-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640662PMC
October 2017

[Cancer immunotherapy via systemic RNA delivery to dendritic cells].

Med Sci (Paris) 2017 Oct 10;33(10):852-856. Epub 2017 Oct 10.

Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS 5286, centre Léon Bérard, centre de recherche en cancérologie de Lyon, Lyon, 69008, France.

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http://dx.doi.org/10.1051/medsci/20173310013DOI Listing
October 2017

Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells.

Front Immunol 2017 7;8:394. Epub 2017 Apr 7.

INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France.

The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DCs (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells. Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM-signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatiotemporal engagement of ITAM- and TLR-signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.
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http://dx.doi.org/10.3389/fimmu.2017.00394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383719PMC
April 2017

A Milestone Review on How Macrophages Affect Tumor Growth.

Cancer Res 2016 11;76(22):6439-6442

Innovation in Immuno-monitoring and Immunotherapy Platform (PI3), Léon Bérard Cancer Center, Lyon, France.

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http://dx.doi.org/10.1158/0008-5472.CAN-16-2631DOI Listing
November 2016

A novel regulation of PD-1 ligands on mesenchymal stromal cells through MMP-mediated proteolytic cleavage.

Oncoimmunology 2016 Mar 29;5(3):e1091146. Epub 2015 Oct 29.

Université de Lyon, Lyon, France; Université Lyon 1, ISPB, Lyon, France; INSERM U1052, Center de Recherche en Cancérologie de Lyon, Lyon, France; CNRS UMR5286, Center de Recherche en Cancérologie de Lyon, Lyon, France.

Whether fibroblasts regulate immune response is a crucial issue in the modulation of inflammatory responses. Herein, we demonstrate that foreskin fibroblasts (FFs) potently inhibit CD3 T cell proliferation through a mechanism involving early apoptosis of activated T cells. Using blocking antibodies, we demonstrate that the inhibition of T cell proliferation occurs through cell-to-cell interactions implicating PD-1 receptor expressed on T cells and its ligands, PD-L1 and PD-L2, on fibroblasts. Dual PD-1 ligand neutralization is required to abrogate (i) binding of the PD-1-Fc fusion protein, (ii) early apoptosis of T cells, and (iii) inhibition of T cell proliferation. Of utmost importance, we provide the first evidence that PD-1 ligand expression is regulated through proteolytic cleavage by endogenous matrix metalloproteinases (MMPs) without transcriptional alteration during culture-time. Using (i) different purified enzymatic activities, (ii) MMP-specific inhibitors, and (iii) recombinant human MMP-9 and MMP-13, we demonstrated that in contrast to CD80/CD86, PD-L1 was selectively cleaved by MMP-13, while PD-L2 was sensitive to broader MMP activities. Their cleavage by exogenous MMP-9 and MMP-13 with loss of PD-1 binding domain resulted in the reversion of apoptotic signals on mitogen-activated CD3 T cells. We suggest that MMP-dependent cleavage of PD-1 ligands on fibroblasts may limit their immunosuppressive capacity and thus contribute to the exacerbation of inflammation in tissues. In contrast, carcinoma-associated fibroblasts appear PD-1 ligand-depleted through MMP activity that may impair physical deletion of exhausted defective memory T cells through apoptosis and facilitate their regulatory functions. These observations should be considered when using the powerful PD-1/PD-L1 blocking immunotherapies.
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http://dx.doi.org/10.1080/2162402X.2015.1091146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839348PMC
March 2016

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo.

Eur J Immunol 2016 Feb 23;46(2):354-9. Epub 2015 Nov 23.

International Center for Infectiology Research (CIRI), Lyon, France.

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.
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http://dx.doi.org/10.1002/eji.201545977DOI Listing
February 2016

pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation.

J Autoimmun 2016 Feb 1;67:8-18. Epub 2015 Sep 1.

Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland. Electronic address:

Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation.
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http://dx.doi.org/10.1016/j.jaut.2015.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758828PMC
February 2016

Breast Cancer Cell-Derived GM-CSF Licenses Regulatory Th2 Induction by Plasmacytoid Predendritic Cells in Aggressive Disease Subtypes.

Cancer Res 2015 Jul 14;75(14):2775-87. Epub 2015 May 14.

INSERM U932, Institut Curie, Paris, France. Institut Curie, Department of Immunology, Paris, France. Center of Clinical Investigations, Curie-IGR, Paris-Villejuif, France.

Reciprocal interactions between tumor cells and their microenvironment vitally impact tumor progression. In this study, we show that GM-CSF produced by primary breast tumor cells induced the activation of plasmacytoid predendritic cells (pDC), a cell type critical to anti-viral immunity. pDC that expressed the GM-CSF receptor were increased in breast tumors compared with noninvolved adjacent breast tissue. Tumor-activated pDC acquired naïve CD4(+) T-cell stimulatory capacity and promoted a regulatory Th2 response. Finally, the concomitant increase of GM-CSF and pDC was significantly associated with relatively more aggressive breast cancer subtypes. Our results characterize the first tumor-derived factor that can activate pDC to promote a regulatory Th2 response, with implications for therapeutic targeting of a tumor-immune axis of growing recognition in its significance to cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2386DOI Listing
July 2015

TLR9 transcriptional regulation in response to double-stranded DNA viruses.

J Immunol 2014 Oct 5;193(7):3398-408. Epub 2014 Sep 5.

International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France;

The stimulation of TLRs by pathogen-derived molecules leads to the production of proinflammatory cytokines. Because uncontrolled inflammation can be life threatening, TLR regulation is important; however, few studies have identified the signaling pathways that contribute to the modulation of TLR expression. In this study, we examined the relationship between activation and the transcriptional regulation of TLR9. We demonstrate that infection of primary human epithelial cells, B cells, and plasmacytoid dendritic cells with dsDNA viruses induces a regulatory temporary negative-feedback loop that blocks TLR9 transcription and function. TLR9 transcriptional downregulation was dependent on TLR9 signaling and was not induced by TLR5 or other NF-κB activators, such as TNF-α. Engagement of the TLR9 receptor induced the recruitment of a suppressive complex, consisting of NF-κBp65 and HDAC3, to an NF-κB cis element on the TLR9 promoter. Knockdown of HDAC3 blocked the transient suppression in which TLR9 function was restored. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR9, immune induction, and inflammation against viruses.
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http://dx.doi.org/10.4049/jimmunol.1400249DOI Listing
October 2014

ICOS is associated with poor prognosis in breast cancer as it promotes the amplification of immunosuppressive CD4 T cells by plasmacytoid dendritic cells.

Oncoimmunology 2013 Mar;2(3):e23185

Université de Lyon; Lyon, France ; ISPB; Université de Lyon 1; Lyon, France ; INSERM U1052; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; CNRS UMR5286; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; LabEx DEVweCAN; Lyon, France ; Centre Léon Bérard; Lyon, France.

Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) that infiltrate primary breast tumors impair patient survival. The ICOS-mediated interaction between tumor-infiltrating CD4 T cells and pDCs leads to the amplification of Tregs and interleukin-10 secretion. Importantly, ICOS cell infiltration correlates with adverse patient prognosis, identifying ICOS as a new target for cancer immunotherapy.
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http://dx.doi.org/10.4161/onci.23185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661154PMC
March 2013

Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment.

Cancer Res 2013 Aug 30;73(15):4629-40. Epub 2013 May 30.

Université de Lyon, Lyon, France.

Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4(+) T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)-9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629-40. ©2013 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3058DOI Listing
August 2013

Plasmacytoid dendritic cells deficient in IFNα production promote the amplification of FOXP3 regulatory T cells and are associated with poor prognosis in breast cancer patients.

Oncoimmunology 2013 Jan;2(1):e22338

Université de Lyon; Lyon, France ; Université Lyon 1; ISPB; Lyon, France ; INSERM U1052; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; CNRS UMR5286; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; LabEx DEVweCAN; Lyon, France ; Centre Léon Bérard; Lyon, France.

The accumulation of plasmacytoid dendritic cells (pDCs) within breast carcinoma lesions is associated with a poor clinical outcome. We demonstrated that the deleterious impact of tumor-associated pDCs (TApDCs) is due to their impaired capacity to produce Type I interferon, which in turn potentiates their ability to sustain the proliferation of immunosuppressive regulatory T cells.
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http://dx.doi.org/10.4161/onci.22338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583914PMC
January 2013

Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells.

Int J Cancer 2013 Aug 8;133(3):771-8. Epub 2013 Mar 8.

Université de Lyon, Lyon, France.

We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor-associated pDC (TApDC) in breast cancer. We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production. The involvment of tumor-derived TGF-β was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF-7 expression and nuclear translocation in pDC after their exposure to tumor-derived supernatants or recombinant TGF-β1 and TNF-α. Our findings indicate that targeting TApDC to restore their IFN-α production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9-based immunotherapy with TGF-β and TNF-α antagonists.
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http://dx.doi.org/10.1002/ijc.28072DOI Listing
August 2013

ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells.

Cancer Res 2012 Dec 1;72(23):6130-41. Epub 2012 Oct 1.

Team 11, Cancer Research Center of Lyon, INSERM, France.

Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-2409DOI Listing
December 2012

Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression.

Cancer Res 2012 Oct 25;72(20):5188-97. Epub 2012 Jul 25.

Université de Lyon, Lyon, France.

Infiltration and dysfunction of immune cells have been documented in many types of cancers. We previously reported that plasmacytoid dendritic cells (pDC) within primary breast tumors correlate with an unfavorable prognosis for patients. The role of pDC in cancer remains unclear but they have been shown to mediate immune tolerance in other pathophysiologic contexts. We postulated that pDC may interfere with antitumor immune response and favor tolerance in breast cancer. The present study was designed to decipher the mechanistic basis for the deleterious impact of pDC on the clinical outcome. Using fresh human breast tumor biopsies (N = 60 patients), we observed through multiparametric flow cytometry increased tumor-associated (TA) pDC (TApDC) rates in aggressive breast tumors, i.e., those with high mitotic index and the so-called triple-negative breast tumors (TNBT). Furthermore, TApDC expressed a partially activated phenotype and produced very low amounts of IFN-α following toll-like receptor activation in vitro compared with patients' blood pDC. Within breast tumors, TApDC colocalized and strongly correlated with TA regulatory T cells (TATreg), especially in TNBT. Of most importance, the selective suppression of IFN-α production endowed TApDC with the unique capacity to sustain FoxP3(+) Treg expansion, a capacity that was reverted by the addition of exogenous IFN-α. These findings indicate that IFN-α-deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo, contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3468DOI Listing
October 2012

Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis.

Oncoimmunology 2012 May;1(3):380-382

Université de Lyon; Lyon, France ; Université Lyon 1; ISPB; Lyon, France ; INSERM; U1052; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; Cnrs; UMR5286; Centre de Recherche en Cancérologie de Lyon; Lyon, France ; LabEx DEVweCAN; Lyon, France ; Department of Medical Oncology; Centre Léon Bérard; Lyon, France.

Using two different and complementary approaches (flow cytometry and immunohistochemistry) on two independent cohorts of ovarian cancer patients, we found that accumulation of plasmacytoid dendritic cells (pDC) in tumors is associated with early relapse. This deleterious effect of tumor-associated pDC was evident when they are present in cancer epithelium but not in lymphoid aggregates.
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http://dx.doi.org/10.4161/onci.18801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382863PMC
May 2012