Biologie intégrative des cellules dendritiques et des cellules T chez l’homme

Publications de l’équipe

Année de publication : 2019

Dimitra Kerdidani, Panagiotis Chouvardas, Ares Rocanin Arjo, Ioanna Giopanou, Giannoula Ntaliarda, Yu Amanda Guo, Mary Tsikitis, Georgios Kazamias, Konstantinos Potaris, Georgios T Stathopoulos, Spyros Zakynthinos, Ioannis Kalomenidis, Vassili Soumelis, George Kollias, Maria Tsoumakidou (2019 Mar 31)

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.

Nature communications : 1405 : DOI : 10.1038/s41467-019-09370-z En savoir plus
Résumé

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

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Année de publication : 2018

Marie Nguyen, Adele De Ninno, Arianna Mencattini, Fanny Mermet-Meillon, Giulia Fornabaio, Sophia S Evans, Mélissande Cossutta, Yasmine Khira, Weijing Han, Philémon Sirven, Floriane Pelon, Davide Di Giuseppe, Francesca Romana Bertani, Annamaria Gerardino, Ayako Yamada, Stéphanie Descroix, Vassili Soumelis, Fatima Mechta-Grigoriou, Gérard Zalcman, Jacques Camonis, Eugenio Martinelli, Luca Businaro, Maria Carla Parrini (2018 Dec 28)

Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments.

Cell reports : 3884-3893.e3 : DOI : S2211-1247(18)31926-0 En savoir plus
Résumé

A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2 breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor. We uncovered the capacity of the drug trastuzumab to specifically promote long cancer-immune interactions (>50 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) antagonized the effects of trastuzumab. These observations constitute a proof of concept that tumors-on-chip are powerful platforms to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level drug responses, and to dissect the roles of stromal components.

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Stéphanie Torrino, Wei-Wei Shen, Cédric M Blouin, Satish Kailasam Mani, Christine Viaris de Lesegno, Pierre Bost, Alexandre Grassart, Darius Köster, Cesar Augusto Valades-Cruz, Valérie Chambon, Ludger Johannes, Paolo Pierobon, Vassili Soumelis, Catherine Coirault, Stéphane Vassilopoulos, Christophe Lamaze (2018 Oct 24)

EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription.

The Journal of cell biology : 4092-4105 : DOI : 10.1083/jcb.201801122 En savoir plus
Résumé

Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress.

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Paula Michea, Floriane Noël, Eve Zakine, Urszula Czerwinska, Philémon Sirven, Omar Abouzid, Christel Goudot, Alix Scholer-Dahirel, Anne Vincent-Salomon, Fabien Reyal, Sebastian Amigorena, Maude Guillot-Delost, Elodie Segura, Vassili Soumelis (2018 Jul 18)

Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific.

Nature immunology : 885-897 : DOI : 10.1038/s41590-018-0145-8 En savoir plus
Résumé

The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14 DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies.

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Alculumbre SG, Saint-André V, Di Domizio J, Vargas P, Sirven P, Bost P, Maurin M, Maiuri P, Wery M, Roman MS, Savey L, Touzot M, Terrier B, Saadoun D, Conrad C, Gilliet M, Morillon A, Soumelis V (2018 Jan 1)

Diversification of human plasmacytoid predendritic cells in response to a single stimulus

Nature Immunology : 19(1) : 63-75 : DOI : 10.1038/s41590-017-0012-z En savoir plus
Résumé

Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells

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Année de publication : 2017

Sylvain Thierry, Wael Jdey, Solana Alculumbre, Vassili Soumelis, Patricia Noguiez-Hellin, Marie Dutreix (2017 Sep 27)

The DNA repair inhibitor Dbait is specific for malignant hematologic cells in blood.

Molecular cancer therapeutics : DOI : molcanther.0405.2017 En savoir plus
Résumé

Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and Platinium salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA, enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1 and U-937) and in normal primary human PBMCs, resting or activated T-cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide range drug with the potential to specifically increase DNA damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation.

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V Soumelis (2017 Aug 15)

Molecular and cellular discoveries in inflammatory dermatoses.

Journal of the European Academy of Dermatology and Venereology : JEADV : 3-7 : DOI : 10.1111/jdv.14373 En savoir plus
Résumé

It was no earlier than 1986 that T helper (Th)1 and Th2 cells were described for the first time, opening the field of lymphocyte diversity and the investigation of the physiopathology of inflammatory diseases such as atopic dermatitis and psoriasis. Since that time, much research has been carried out showing a very complex communication network leading to inflammatory responses. Nowadays, understanding the cellular and molecular components of the inflammatory network and of the different crosstalks not only for groups of diseases but also for the individual patient is mandatory for developing and personalizing treatments. The aim of the present proceeding was to provide an update concerning some of the most recent molecular and cellular discoveries in inflammatory skin diseases and especially of AD.

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Lucia Pattarini, Coline Trichot, Sofia Bogiatzi, Maximilien Grandclaudon, Stephan Meller, Zela Keuylian, Melanie Durand, Elisabetta Volpe, Stefania Madonna, Andrea Cavani, Andrea Chiricozzi, Marco Romanelli, Toshiyuki Hori, Alain Hovnanian, Bernhard Homey, Vassili Soumelis (2017 Apr 22)

TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand.

The Journal of experimental medicine : 1529-1546 : DOI : 10.1084/jem.20150402 En savoir plus
Résumé

T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC-polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.

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Elodie Segura, Vassili Soumelis (2017 Mar 23)

Of Human DC Migrants and Residents.

Immunity : 342-344 : DOI : S1074-7613(17)30087-0 En savoir plus
Résumé

Migration from peripheral tissues to lymph nodes is a key feature of dendritic cells (DCs), but little is known about the migration patterns of human DCs. By analyzing multiple lymphoid organs and tissues from the same donors, Granot et al. propose that the two main subsets of human DCs display different migratory capacity.

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Lucia Pattarini, Vassili Soumelis (2017 Feb 16)

Keeping skin inflammation local.

Nature immunology : 250-251 : DOI : 10.1038/ni.3687 En savoir plus
Résumé

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Clémence Granier, Vassili Soumelis, Marion Mandavit, Laure Gibault, Radia Belazzoug, Eléonore de Guillebon, Cécile Badoual, Eric Tartour, Hélène Roussel (2017 Feb 6)

[The « immune checkpoints », how does it work].

Annales de pathologie : 18-28 : DOI : S0242-6498(16)30174-2 En savoir plus
Résumé

Costimulatory molecules allow the full lymphocyte activation, whereas co-inhibitory molecules are negative counterparts that act as immune regulators, avoiding excessive response. In some context of chronic inflammation such as cancer, co-inhibitory immune checkpoint as CTLA-4, PD-1, Lag-3, Tim-3 can accumulate at the membrane of T cells leading to a state of anergy and therefore the loss of tumor growth control. Consequently, these immune checkpoints are considered as potential target in the treatment of cancer. Immunotherapy by anti-CTLA-4 and anti-PD-1/PD-L1 early demonstrated very good proof of efficacy in the setting of several cancers types, supporting the role of these molecules in tumor immune escape. The aim of this review is to summarize the pathophysiology of immune checkpoints and their therapeutic applications in cancer.

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Année de publication : 2016

Cristina Ghirelli, Benjamin Sadacca, Fabien Reyal, Raphaël Zollinger, Paula Michea, Philémon Sirven, Lucia Pattarini, Carolina Martínez-Cingolani, Maude Guillot-Delost, André Nicolas, Alix Scholer-Dahirel, Vassili Soumelis (2016 Sep 14)

No evidence for TSLP pathway activity in human breast cancer.

Oncoimmunology : e1178438 : DOI : 10.1080/2162402X.2016.1178438 En savoir plus
Résumé

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that primes dendritic cells for Th2 induction. It has been implicated in different types of allergic diseases. Recent work suggested that TSLP could play an important role in the tumor microenvironment and influence tumor progression, in particular in breast cancer. In this study we systematically assessed the production of TSLP at the mRNA and protein levels in several human breast cancer cell lines, large-scale public transcriptomics data sets, and primary human breast tumors. We found that TSLP production was marginal, and concerned less than 10% of the tumors, with very low mRNA and protein levels. In most cases TSLP was undetectable and found to be expressed at lower levels in breast cancer as compared to normal breast tissue. Last, we could not detect any functional TSLP receptor (TSLPR) expression neither on hematopoietic cells nor on stromal cells within the primary tumor microenvironment. We conclude that TSLP-TSLPR pathway activity is not significantly detected within human breast cancer. Taken together, these observations do not support TSLP targeting in breast cancer.

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Maude Guillot-Delost, Lia Guilleré, Frédérique Berger, Aurore Ventre, Paula Michea, Philémon Sirven, Lucia Pattarini, Alix Scholer-Dahirel, Fatima-Zahra Kebir, Michel Huerre, Olfa Chouchane-Mlik, Emmanuelle Lappartient, José Rodriguez, Thomas Jouffroy, Jerzy Klijanienko, André Nicolas, Xavier Sastre-Garau, Sofia Honorio, Véronique Mosseri, Nelly Le Peltier, Marie-Paule Sablin, Christophe Le Tourneau, Éric Tartour, Cécile Badoual, Vassili Soumelis (2016 Sep 14)

Ligand-receptor dissociated expression explains high TSLP without prognostic impact in human primary head and neck squamous cell carcinoma.

Oncoimmunology : e1179414 : DOI : 10.1080/2162402X.2016.1179414 En savoir plus
Résumé

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine expressed by epithelial cells during allergic inflammation, and activating dendritic cells (DC). Its expression and functional role in cancer remain controversial. We conducted retrospective (n = 89), and prospective studies including patients with untreated primary head and neck squamous cell carcinoma (HNSCC). We found that TSLP was overexpressed by HNSCC tumor cells, and associated with a highly differentiated status. However, no significant difference in overall and recurrence-free survival was found between patients bearing a tumor with high and low TSLP levels, respectively. Surprisingly, there was no significant association between the levels of TSLP expression, and the number of tumor-infiltrating mature DCLAMP(+) DC. In order to explain the apparent lack of TSLP-induced DC activation, we performed phenotypic and functional experiments on freshly resected tumors. Tumor-infiltrating immune cells, including DC, did not express the TSLP receptor heterodimer (TSLPR chain, IL-7Ralpha chain). Furthermore, freshly sorted blood CD11c(+) DC from healthy donors cultured with tumor-conditioned supernatant exhibited an activated profile, but this was not affected by an anti-TSLP blocking antibody, suggesting a DC activation pathway independent of tumor-derived TSLP. Overall, our results demonstrate that TSLP is overexpressed in HNSCC but its function is hampered by the lack of TSLPR-expressing cells in the tumor microenvironment. Such a dissociated ligand-receptor expression may impact intercellular communication in other immune activation pathways, and tumor types.

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Année de publication : 2015

Cristina Ghirelli, Fabien Reyal, Marine Jeanmougin, Raphaël Zollinger, Philémon Sirven, Paula Michea, Christophe Caux, Nathalie Bendriss-Vermare, Marie-Hélène Donnadieu, Martial Caly, Virginie Fourchotte, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, Xavier Sastre-Garau, Vassili Soumelis (2015 May 16)

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

Cancer research : 2775-87 : DOI : 10.1158/0008-5472.CAN-14-2386 En savoir plus
Résumé

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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Antonio Cappuccio, Raphaël Zollinger, Mirjam Schenk, Aleksandra Walczak, Nicolas Servant, Emmanuel Barillot, Philippe Hupé, Robert L Modlin, Vassili Soumelis (2015 Apr 21)

Combinatorial code governing cellular responses to complex stimuli.

Nature communications : 6847 : DOI : 10.1038/ncomms7847 En savoir plus
Résumé

Cells adapt to their environment through the integration of complex signals. Multiple signals can induce synergistic or antagonistic interactions, currently considered as homogenous behaviours. Here, we use a systematic theoretical approach to enumerate the possible interaction profiles for outputs measured in the conditions 0 (control), signals X, Y, X+Y. Combinatorial analysis reveals 82 possible interaction profiles, which we biologically and mathematically grouped into five positive and five negative interaction modes. To experimentally validate their use in living cells, we apply an original computational workflow to transcriptomics data of innate immune cells integrating physiopathological signal combinations. Up to 9 of the 10 defined modes coexisted in context-dependent proportions. Each interaction mode was preferentially used in specific biological pathways, suggesting a functional role in the adaptation to multiple signals. Our work defines an exhaustive map of interaction modes for cells integrating pairs of physiopathological and pharmacological stimuli.

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