Integrative Biology of Human Dendritic Cells and T Cells

Team Publications

Year of 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 Learn more
Summary

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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Year of 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 Learn more
Summary

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 Learn more
Summary

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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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 Learn more
Summary

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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Year of 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 Learn more
Summary

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 Learn more
Summary

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 Learn more
Summary

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 Learn more
Summary

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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Year of 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 Learn more
Summary

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 Learn more
Summary

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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Year of publication 2014

Maxime Touzot, Maximilien Grandclaudon, Antonio Cappuccio, Takeshi Satoh, Carolina Martinez-Cingolani, Nicolas Servant, Nicolas Manel, Vassili Soumelis (2014 May 29)

Combinatorial flexibility of cytokine function during human T helper cell differentiation.

Nature communications : 3987 : DOI : 10.1038/ncomms4987 Learn more
Summary

In an inflammatory microenvironment, multiple cytokines may act on the same target cell, creating the possibility for combinatorial interactions. How these may influence the system-level function of a given cytokine is unknown. Here we show that a single cytokine, interferon (IFN)-alpha, can generate multiple transcriptional signatures, including distinct functional modules of variable flexibility, when acting in four cytokine environments driving distinct T helper cell differentiation programs (Th0, Th1, Th2 and Th17). We provide experimental validation of a chemokine, cytokine and antiviral modules differentially induced by IFN-α in Th1, Th2 and Th17 environments. Functional impact is demonstrated for the antiviral response, with a lesser IFN-α-induced protection to HIV-1 and HIV-2 infection in a Th17 context. Our results reveal that a single cytokine can induce multiple transcriptional and functional programs in different microenvironments. This combinatorial flexibility creates a previously unrecognized diversity of responses, with potential impact on disease physiopathology and cytokine therapy.

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