03 / 04 / 2021
Cell
Maturation and persistence of the anti-SARS-CoV-2 memory B cell response
Sokal A, Chappert P, Barba-Spaeth G, Roeser A, Fourati S, Azzaoui I, Vandenberghe A, Fernandez I, Meola A, Bouvier-Alias M, Crickx E, Beldi-Ferchiou A, Hue S, Languille L, Michel M, Baloul S, Noizat-Pirenne F, Luka M, Mégret J, Ménager M, Pawlotsky JM, Fillatreau S, Rey FA, Weill JC, Reynaud CA, Mahévas M.
Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.
03 / 04 / 2021
The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages
Zhiqiang Huang, Ning Liang, Saioa Goñi, Anastasios Damdimopoulos, Cheng Wang, Raphaelle Ballaire, Jennifer Jager, Henri Niskanen,...
While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation...
02 / 12 / 2021
Expand to shield: IL-15 and in situ lymphocytic proliferation
Gabriela Bindea, Bernhard Mlecnik, Jérôme Galon
The tumor microenvironment includes a complex network of cytokines and chemokines that contribute to shaping the intratumoral immune reaction. Understanding the mechanisms leading to immune-hot (Immunoscore-high) altered (excluded and immunosuppressed) and cold tumors are of critical importance for successful anti-cancer therapies. Two essential mechanisms are highlighted. Specific chemokines and adhesion molecules appeared to target and attract immune effector T cells to the tumor microenvironment and to specific regions within the tumor. These mechanisms are dependent upon intratumoral IL-15 expression. Decreased IL15 expression also affected the local proliferation of B and T lymphocytes. A comprehensive analysis revealed a major contribution of IL15 in shaping the tumor immune contexture...
02 / 02 / 2021
Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction
Sofia Giacosa, Catherine Pillet, Irinka Séraudie, Laurent Guyon, Yann Wallez, Caroline Roelants, Christophe Battail, Bertrand Evrard,...
Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL- cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug-gene pairs...
01 / 28 / 2021
The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival
Elise F Nassif, Bernhard Mlecnik, Constance Thibault, Marie Auvray, Daniela Bruni, Alexandre Colau, Eva Compérat, Gabriela Bindea,...
Background-The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. Methods-This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS...
12 / 30 / 2020
Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth
Daniel J Owens, Julien Messéant, Sophie Moog, Mark Viggars, Arnaud Ferry, Kamel Mamchaoui, Emmanuelle Lacène, Norma Roméro, Astrid Brull, Gisèle Bonne, Gillian Butler-Browne, Catherine Coirault
Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes...
