Biology

The immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A has been puzzling scientific and clinical communities for more than 3 decades. Indeed, the development of inhibitory antibodies to FVIII remains a major clinical challenge and is associated with enormous societal costs. Thus, the reasons for which a presumably innocuous, short-lived, intravenously administered glycoprotein triggers such a deleterious, long-lasting neutralizing immune response is an enigma. This review does not pretend to bring an answer to this challenging question. It will however summarize the latest findings regarding the molecular interactions at play in the recognition of FVIII by the immune cells, the validity of the proposed risk factors for FVIII alloimmunization, and the different solutions that allow induction of FVIII-specific tolerance in preclinical models of hemophilia A.

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical outcome for hospitalized patients remains a major challenge. Immunophenotyping and transcriptomic analysis of hospitalized COVID-19 patients at admission allow identifying the two categories of patients. Inflammation, high neutrophil activation, dysfunctional monocytic response and a strongly impaired adaptive immune response was observed in patients who will experience the more severe form of the disease. This observation was validated in an independent cohort of patients. Using in silico analysis on drug signature database, we identify differential therapeutics that specifically correspond to each group of patients. From this signature, we...

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4+ lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4+ plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we dete...

BackgroundNatural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype.ObjectiveWe aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME.MethodsNK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs.ResultsIn the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX...

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs’ functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver,...

The immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A has been puzzling scientific and clinical communities for more than 3 decades. Indeed, the development of inhibitory antibodies to FVIII remains a major clinical challenge and is associated with enormous societal costs. Thus, the reasons for which a presumably innocuous, short‐lived, intravenously administered glycoprotein triggers such a deleterious, long‐lasting neutralizing immune response is an enigma. This review does not pretend to bring an answer to this challenging question. It will however summarize the latest findings regarding the molecular interactions at play in the recognition of FVIII by the immune cells, the validity of the proposed risk factors for FVIII alloimmunization, and the different solutions that allow induction of FVIII‐specific tolerance in preclinical models of hemophilia A.

L’hemophilie A est une maladie hemorragique rare liee a une absence de facteur VIII (FVIII) fonctionnel de la coagulation. Les formes les plus severes engendrent l’apparition d’hemorragies spontanees, pouvant mettre en jeu le pronostic vital. La prevention et le traitement des saignements se fait par injection de FVIII therapeutique. Ce FVIII recombinant est difficile a produire, sa demi-vie est courte et la frequence des injections impacte la qualite de vie des patients. De plus, chez 25 a 35% d’entre eux, l’injection de FVIII exogene provoque l’apparition d’anticorps anti-FVIII qui neutralisent son activite pro-coagulante et sont donc appeles « inhibiteurs ». Au cours de ma these, j’ai tout d’abord valide in vivo une nouvelle strategie therapeutique, alternative a la therapie de substitution et qui repose sur l’injection d’ARNm codant le FVIII (Article 1). Dans le deuxieme volet, j’ai etudie la possibilite de prevenir la reponse immunitaire anti-FVIII par inhibition des lymphocyte...

L’hémophilie A est une maladie hémorragique rare liée à une absence de facteur VIII (FVIII) fonctionnel de la coagulation. Les formes les plus sévères engendrent l’apparition d’hémorragies spontanées, pouvant mettre en jeu le pronostic vital. La prévention et le traitement des saignements se fait par injection de FVIII thérapeutique. Ce FVIII recombinant est difficile à produire, sa demi-vie est courte et la fréquence des injections impacte la qualité de vie des patients. De plus, chez 25 à 35% d’entre eux, l’injection de FVIII exogène provoque l’apparition d’anticorps anti-FVIII qui neutralisent son activité pro-coagulante et sont donc appelés « inhibiteurs ». Au cours de ma thèse, j’ai tout d’abord validé in vivo une nouvelle stratégie thérapeutique, alternative à la thérapie de substitution et qui repose sur l’injection d’ARNm codant le FVIII (Article 1). Dans le deuxième volet, j’ai étudié la possibilité de prévenir la réponse immunitaire anti-FVIII par inhibition des lymphocyte...

One billion people worldwide get flu every year, including patients with non–small cell lung cancer (NSCLC). However, the impact of acute influenza A virus (IAV) infection on the composition of the tumor microenvironment (TME) and the clinical outcome of patients with NSCLC is largely unknown. We set out to understand how IAV load impacts cancer growth and modifies cellular and molecular players in the TME. Herein, we report that IAV can infect both tumor and immune cells, resulting in a long-term protumoral effect in tumor-bearing mice. Mechanistically, IAV impaired tumor-specific T-cell responses, led to the exhaustion of memory CD8+ T cells and induced PD-L1 expression on tumor cells. IAV infection modulated the transcriptomic profile of the TME, fine-tuning it toward immunosuppression, carcinogenesis, and lipid and drug metabolism. Consistent with these data, the transcriptional module induced by IAV infection in tumor cells in tumor-bearing mice was also found in human patients...