Réponses immunitaires et cancer

Publications de l’équipe

Année de publication : 2020

Pace L1, Amigorena S2. (2020 Feb 14)

Epigenetics of T cell fate decision.

Current opinion in immunology : 63 : Curr Opin Immunol. 2020 Feb 14;63:43-50. doi: 10.1016/j.coi.2020.01.002. [Epub ahead of print] : 43,50 : DOI : 10.1016/j.coi.2020.01.002 En savoir plus
Résumé

The changes of transcription factor activity and chromatin dynamics guide functional differentiation of T cell subsets, including commitment to short-lived effectors and long-term survival of memory T cells. Understanding the lineage relationships among the different stages of effector and memory differentiation has profound therapeutic implications for the development of new vaccine and immunotherapy protocols. Here we review the contribution of chromatin architecture to T cell specification, focusing on the interplay between epigenetic changes and transcriptional programs linked to T cell plasticity, commitment and memory. We will also discuss the translational implications of epigenetic control in the context of infections and cancer.

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Année de publication : 2019

Gehrmann U1,2, Burbage M3, Zueva E3, Goudot C3, Esnault C4, Ye M3, Carpier JM3, Burgdorf N3, Hoyler T3, Suarez G3, Joannas L3, Heurtebise-Chrétien S3, Durand S5,6, Panes R7,8, Bellemare-Pelletier A8, Sáez PJ3, Aprahamian F5,6, Lefevre D5,6, Adoue V9, Zine El Aabidine A4, Muhammad Ahmad M4, Hivroz C3, Joffre O10, Cammas F11,12, Kroemer G5,6,13,14,15, Gagnon E7,8, Andrau JC4, Amigorena S1. (2019 Dec 17)

Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation.

Proceedings of the National Academy of Sciences : 116 : Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25839-25849. doi: 10.1073/pnas.1901639116. Epub 2019 Nov 27. : 25839,25849 : DOI : 10.1073/pnas.1901639116 En savoir plus
Résumé

Naive CD4+ T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4+ T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28-/- T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28-/- regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.

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Kondratova M1, Czerwinska U1,2, Sompairac N1,2, Amigorena SD3, Soumelis V3, Barillot E1, Zinovyev A1, Kuperstein I4. (2019 Oct 22)

A multiscale signalling network map of innate immune response in cancer reveals cell heterogeneity signatures.

Nature communications : 10 : Nat Commun. 2019 Oct 22;10(1):4808. doi: 10.1038/s41467-019-12270-x. : 4808 : DOI : 10.1038/s41467-019-12270-x En savoir plus
Résumé

The lack of integrated resources depicting the complexity of the innate immune response in cancer represents a bottleneck for high-throughput data interpretation. To address this challenge, we perform a systematic manual literature mining of molecular mechanisms governing the innate immune response in cancer and represent it as a signalling network map. The cell-type specific signalling maps of macrophages, dendritic cells, myeloid-derived suppressor cells and natural killers are constructed and integrated into a comprehensive meta map of the innate immune response in cancer. The meta-map contains 1466 chemical species as nodes connected by 1084 biochemical reactions, and it is supported by information from 820 articles. The resource helps to interpret single cell RNA-Seq data from macrophages and natural killer cells in metastatic melanoma that reveal different anti- or pro-tumor sub-populations within each cell type. Here, we report a new open source analytic platform that supports data visualisation and interpretation of tumour microenvironment activity in cancer.

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Année de publication : 2017

Goudot C1, Coillard A1, Villani AC2, Gueguen P1, Cros A1, Sarkizova S3, Tang-Huau TL4, Bohec M5, Baulande S5, Hacohen N2, Amigorena S1, Segura E6. (2019 Sep 19)

Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages.

Immunity : 47 : Immunity. 2017 Sep 19;47(3):582-596.e6. doi: 10.1016/j.immuni.2017.08.016. : 582,596 : DOI : 10.1016/j.immuni.2017.08.016 En savoir plus
Résumé

After entering tissues, monocytes differentiate into cells that share functional features with either macrophages or dendritic cells (DCs). How monocyte fate is directed toward monocyte-derived macrophages (mo-Macs) or monocyte-derived DCs (mo-DCs) and which transcription factors control these differentiation pathways remains unknown. Using an in vitro culture model yielding human mo-DCs and mo-Macs closely resembling those found in vivo in ascites, we show that IRF4 and MAFB were critical regulators of monocyte differentiation into mo-DCs and mo-Macs, respectively. Activation of the aryl hydrocarbon receptor (AHR) promoted mo-DC differentiation through the induction of BLIMP-1, while impairing differentiation into mo-Macs. AhR deficiency also impaired the in vivo differentiation of mouse mo-DCs. Finally, AHR activation correlated with mo-DC infiltration in leprosy lesions. These results establish that mo-DCs and mo-Macs are controlled by distinct transcription factors and show that AHR acts as a molecular switch for monocyte fate specification in response to micro-environmental factors.

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Année de publication : 2019

Antonela Merlotti, Alvaro López Malizia, Paula Michea, Pierre-Emmanuel Bonte, Christel Goudot, María Sol Carregal, Nicolás Nuñez, Christine Sedlik, Ana Ceballos, Vassili Soumelis, Sebastián Amigorena, Jorge Geffner, Eliane Piaggio, Juan Sabatte (2019 Aug 21)

Aberrant fucosylation enables breast cancer clusterin to interact with dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN).

Oncoimmunology : e1629257 : DOI : 10.1080/2162402X.2019.1629257 En savoir plus
Résumé

Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.

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Coillard A1,2, Segura E1. (2019 Aug 13)

In vivo Differentiation of Human Monocytes.

Frontiers in immunology : 10 : 1907 : DOI : 10.3389/fimmu.2019.01907 En savoir plus
Résumé

Circulating monocytes can infiltrate mucosal or inflamed tissues where they differentiate into either macrophages or dendritic cells. This paradigm is supported by numerous studies conducted in mice and in different in vitro settings for human cells. Determining whether it holds true in vivo in humans is essential for the successful design of monocyte-targeting therapies. Despite limitations inherent to working with human samples, there is accumulating evidence of the existence of in vivo-generated monocyte-derived cells in humans. Here, we review recent studies showing the recruitment of human monocytes into tissues and their differentiation into macrophages or dendritic cells, in normal or pathological settings. We examine the methods available in human studies to demonstrate the monocytic origin of infiltrating cells. Finally, we review the functions of human monocyte-derived cells and how they might contribute to pathogeny.

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Année de publication : 2015

Bonsang-Kitzis H1, Sadacca B2, Hamy-Petit AS3, Moarii M4, Pinheiro A3, Laurent C3, Reyal F1. (2019 Jun 24)

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis.

Oncoimmunology : 5 : 1061176 : DOI : 10.1080/2162402X.2015.1061176 En savoir plus
Résumé

Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52], p = 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions.

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Année de publication : 2019

Mélanie Durand, Thomas Walter, Tiphène Pirnay, Thomas Naessens, Paul Gueguen, Christel Goudot, Sonia Lameiras, Qing Chang, Nafiseh Talaei, Olga Ornatsky, Tatiana Vassilevskaia, Sylvain Baulande, Sebastian Amigorena, Elodie Segura (2019 May 11)

Human lymphoid organ cDC2 and macrophages play complementary roles in T follicular helper responses.

The Journal of experimental medicine : DOI : jem.20181994 En savoir plus
Résumé

CD4 T follicular helper (Tfh) cells are essential for inducing efficient humoral responses. T helper polarization is classically orientated by dendritic cells (DCs), which are composed of several subpopulations with distinct functions. Whether human DC subsets display functional specialization for Tfh polarization remains unclear. Here we find that tonsil cDC2 and CD14 macrophages are the best inducers of Tfh polarization. This ability is intrinsic to the cDC2 lineage but tissue dependent for macrophages. We further show that human Tfh cells comprise two effector states producing either IL-21 or CXCL13. Distinct mechanisms drive the production of Tfh effector molecules, involving IL-12p70 for IL-21 and activin A and TGFβ for CXCL13. Finally, using imaging mass cytometry, we find that tonsil CD14 macrophages localize in situ in the B cell follicles, where they can interact with Tfh cells. Our results indicate that human lymphoid organ cDC2 and macrophages play complementary roles in the induction of Tfh responses.

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Marianne Burbage, Marine Gros, Sebastian Amigorena (2019 Apr 3)

Translate less, prime better, to improve anti-tumor responses.

Nature immunology : DOI : 10.1038/s41590-019-0371-8 En savoir plus
Résumé

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Matteo Gentili, Xavier Lahaye, Francesca Nadalin, Guilherme P F Nader, Emilia Puig Lombardi, Solène Herve, Nilushi S De Silva, Derek C Rookhuizen, Elina Zueva, Christel Goudot, Mathieu Maurin, Aurore Bochnakian, Sebastian Amigorena, Matthieu Piel, Daniele Fachinetti, Arturo Londoño-Vallejo, Nicolas Manel (2019 Mar 28)

The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus.

Cell reports : 3798 : DOI : S2211-1247(19)30365-1 En savoir plus
Résumé

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Paola Bonaventura, Tala Shekarian, Vincent Alcazer, Jenny Valladeau-Guilemond, Sandrine Valsesia-Wittmann, Sebastian Amigorena, Christophe Caux, Stéphane Depil (2019 Feb 26)

Cold Tumors: A Therapeutic Challenge for Immunotherapy.

Frontiers in immunology : 168 : DOI : 10.3389/fimmu.2019.00168 En savoir plus
Résumé

Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called « cold tumors. » In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition,  »supra-physiological » therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors.

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Marine Gros, Sebastian Amigorena (2019 Feb 13)

Regulation of Antigen Export to the Cytosol During Cross-Presentation.

Frontiers in immunology : 41 : DOI : 10.3389/fimmu.2019.00041 En savoir plus
Résumé

Cross-priming refers to the induction of primary cytotoxic CD8 T cell responses to antigens that are not expressed in antigen presenting cells (APCs) responsible for T cell priming. Cross-priming is achieved through cross-presentation of exogenous antigens derived from tumors, extracellular pathogens or infected neighboring cells on Major Histocompatibility Complex (MHC) class I molecules. Despite extensive research efforts to understand the intracellular pathways involved in antigen cross-presentation, certain critical steps remain elusive and controversial. Here we review recent advances on antigen cross-presentation, focusing on the mechanisms involved in antigen export to the cytosol, a crucial step of this pathway.

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Véronique Adoue, Bénédicte Binet, Agathe Malbec, Joanna Fourquet, Paola Romagnoli, Joost P M van Meerwijk, Sebastian Amigorena, Olivier P Joffre (2019 Feb 10)

The Histone Methyltransferase SETDB1 Controls T Helper Cell Lineage Integrity by Repressing Endogenous Retroviruses.

Immunity : 629-644.e8 : DOI : S1074-7613(19)30003-2 En savoir plus
Résumé

Upon activation, naive CD4 T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1 naive CD4 T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1 Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of the repressive H3K9me3 mark at a restricted and cell-type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes. Refined bioinformatic analyses suggest that these retrotransposons regulate Th1 gene cis-regulatory elements or act as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures Th cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.

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Année de publication : 2018

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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Tsing-Lee Tang-Huau, Paul Gueguen, Christel Goudot, Mélanie Durand, Mylène Bohec, Sylvain Baulande, Benoit Pasquier, Sebastian Amigorena, Elodie Segura (2018 Jul 4)

Human in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway.

Nature communications : 2570 : DOI : 10.1038/s41467-018-04985-0 En savoir plus
Résumé

Presentation of exogenous antigens on MHC-I molecules, termed cross-presentation, is essential for cytotoxic CD8 T cell responses. In mice, dendritic cells (DCs) that arise from monocytes (mo-DCs) during inflammation have a key function in these responses by cross-presenting antigens locally in peripheral tissues. Whether human naturally-occurring mo-DCs can cross-present is unknown. Here, we use human mo-DCs and macrophages directly purified from ascites to address this question. Single-cell RNA-seq data show that ascites CD1c DCs contain exclusively monocyte-derived cells. Both ascites mo-DCs and monocyte-derived macrophages cross-present efficiently, but are inefficient for transferring exogenous proteins into their cytosol. Inhibition of cysteine proteases, but not of proteasome, abolishes cross-presentation in these cells. We conclude that human monocyte-derived cells cross-present exclusively using a vacuolar pathway. Finally, only ascites mo-DCs provide co-stimulatory signals to induce effector cytotoxic CD8 T cells. Our findings thus provide important insights on how to harness cross-presentation for therapeutic purposes.

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