Étude du rôle du système du complément dans le développement tumoral

Le système du complément fait partie intégrante du système immunitaire et permet via ses capacités d'opsonisation, de chimiotactisme et de lyse, de protéger l'hôte contre les pathogènes. Compte tenu de ces propriétés, le système du complément a longtemps été considéré comme un élément anti-tumoral. Cependant de récentes études, ont permis de repositionner ce système en montrant des effets pro-tumoraux associés au complément dans certains types de cancer et notamment à travers une modulation de la prolifération tumorale, l'angiogenèse ou le microenvironnement immunitaire. Ces effets peuvent être liés à un mode d'action extracellulaire des protéines du complément mais également à une action non conventionnelle en intracellulaire. Ainsi, le but de mon projet de recherche est de déterminer l'impact pronostique du complément dans la progression tumorale et de comprendre les mécanismes sous-jacents avec pour objectif l'identification de nouveaux marqueurs pronostiques et de nouvelles cibles thérapeutiques. Pour répondre à cette question, nous avons utilisé des outils bioinformatiques, des modèles in vitro, in vivo ainsi que différentes cohortes de patients. Une analyse transcriptomique pan-cancer a permis de mettre en évidence une hétérogénéité de l'expression des gènes du complément dans plus de 30 types de cancers différents. Parmi ces gènes, les gènes de la voie classique et de la voie alterne se trouvent fortement exprimés et associés à un rôle protecteur ou agressif du complément selon le type tumoral. Le carcinome rénal à cellules claires (ccRCC) fait partie des tumeurs présentant une surexpression des gènes du complément associée à un mauvais pronostic. Dans différentes cohortes de patients atteints de ccRCC, nous avons pu mettre en évidence une activation locale de la voie classique associée à une diminution de la survie des patients. Cette activation résulte d'une interaction dynamique entre les cellules tumorales et le microenvironnement immunitaire en présence de complexes immuns. De plus, le complément peut également avoir une action indépendante de la cascade du complément. Nos études ont montré que le Facteur H et le C1s pouvaient exercer des fonctions intrinsèques non canoniques en modifiant les caractéristiques cellulaires clés de la cellule tumorale telles que ; la prolifération, la survie, la migration ou encore le métabolisme. L'ensemble de ces données révèlent le potentiel du système du complément en tant que marqueur pronostique et cible thérapeutique.The complement system is a component of the innate immune system and is involved in cell homeostasis and defense against pathogens through its opsonization, chemotaxis and lysis actions. According to these properties, the complement system has been for long considered as an anti-tumoral effector. However, recent studies have highlighted that complement can also have pro-tumoral effects by promoting tumor cell proliferation, angiogenesis and immunosuppressive microenvironment. These actions can be linked to a classical extracellular mode of action of complement proteins but also to an unconventional intracellular action. The objective of my phD project is to characterize the prognostic impact of complement in tumor progression and understand the mechanism behind this effect with the ultimate goal of identifying new prognostic biomarker or therapeutic targets. To answer this question, bioinformatic, in vitro, in vivo tools and cohorts of patients are used. A pan-cancer transcriptomic analysis reveals a high heterogeneity of the expression of complement genes in more than 30 different tumor types. Among the genes, classical pathway and alternative pathway genes are found strongly expressed and are associated with aggressive or protective effects depending on cancer type. The clear cell renal cell carcinoma (ccRCC) belongs to the tumor with high expression of complement genes that are associated with bad prognosis. In different cohorts of ccRCC patients, we show that a local activation of the classical pathway occurs and it is associated with a decrease survival. This activation results form a dynamic interaction between tumor cells and immune microenvironment in presence of immune complexes. Moreover, the complement system can also play a role outside the cascade. Our studies show that Factor H and C1s exert non canonical intrinsic functions by modulating the key cellular characteristics of tumor cells such as; its metabolism, proliferation, survival or migration. Taking together, these data suggest that the complement system can be a good prognostic biomarker and a therapeutic target with great potential

Complement System: Promoter or Suppressor of Cancer Progression?

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients

Context-dependent roles of complement in cancers

International audienceThe tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient’s clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling.Introductio

Le système du complément

Le système du complément est un composant du système immunitaire inné qui joue un rôle clé dans l’élimination des pathogènes et dans l’homéostasie. Par ses propriétés, ce système a longtemps été considéré comme participant à la réponse anti-tumorale. Cependant, de récentes études ont permis de repositionner le complément en révélant ses effets pro-tumoraux, plus particulièrement des anaphylatoxines C3a et C5a, dans une grande variété de cancers. Ces protéines agissent en effet à différents niveaux de la progression tumorale, que ce soit au sein des cellules tumorales, sur l’angiogenèse ou sur le microenvironnement immunitaire

Dossiers de jurisprudence

Loyer-Larher Christianne, Barrez Claudine, Daugan Gilles, Durfort Sylvie, Cartron Anne-Sylvie, Feuillet-Le Mintier Brigitte, Meledo-Briand Danièle, Rolland-Jacob Marie-Odile. Dossiers de jurisprudence. In: Revue Judiciaire de l'Ouest, 1985-1. pp. 100-134

P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner

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Characterization of Renal Injury and Inflammation in an Experimental Model of Intravascular Hemolysis

Intravascular erythrocyte destruction, accompanied by the release of pro-oxidative and pro-inflammatory components hemoglobin and heme, is a common event in the pathogenesis of numerous diseases with heterogeneous etiology and clinical features. A frequent adverse effect related to massive hemolysis is the renal injury and inflammation. Nevertheless, it is still unclear whether heme––a danger-associated molecular pattern––and ligand for TLR4 or upstream hemolysis-derived products are responsible for these effects. Well-characterized animal models of hemolysis with kidney impairment are needed to investigate how hemolysis drives kidney injury and to test novel therapeutic strategies. Here, we characterized the pathological processes leading to acute kidney injury and inflammation during massive intravascular hemolysis, using a mouse model of phenylhydrazine (PHZ)-triggered erythrocyte destruction. We observed profound changes in mRNA levels for markers of tubular damage (Kim-1, NGAL) and regeneration (indirect marker of tubular injury, Ki-67), and tissue and vascular inflammation (IL-6, E-selectin, P-selectin, ICAM-1) in kidneys of PHZ-treated mice, associated with ultrastructural signs of tubular injury. Moreover, mass spectrometry revealed presence of markers of tubular damage in urine, including meprin-α, cytoskeletal keratins, α-1-antitrypsin, and α-1-microglobulin. Signs of renal injury and inflammation rapidly resolved and the renal function was preserved, despite major changes in metabolic parameters of PHZ-injected animals. Mechanistically, renal alterations were largely heme-independent, since injection of free heme could not reproduce them, and scavenging heme with hemopexin in PHZ-administered mice could not prevent them. Reduced overall health status of the mice suggested multiorgan involvement. We detected amylasemia and amylasuria, two markers of acute pancreatitis. We also provide detailed characterization of renal manifestations associated with acute intravascular hemolysis, which may be mediated by hemolysis-derived products upstream of heme release. This analysis provides a platform for further investigations of hemolytic diseases and associated renal injury and the evaluation of novel therapeutic strategies that target intravascular hemolysis

Characterization of Renal Injury and Inflammation in an Experimental Model of Intravascular Hemolysis

International audienceIntravascular erythrocyte destruction, accompanied by the release of pro-oxidative and pro-inflammatory components hemoglobin and heme, is a common event in the pathogenesis of numerous diseases with heterogeneous etiology and clinical features. A frequent adverse effect related to massive hemolysis is the renal injury and inflammation. Nevertheless, it is still unclear whether heme––a danger-associated molecular pattern––and ligand for TLR4 or upstream hemolysis-derived products are responsible for these effects. Well-characterized animal models of hemolysis with kidney impairment are needed to investigate how hemolysis drives kidney injury and to test novel therapeutic strategies. Here, we characterized the pathological processes leading to acute kidney injury and inflammation during massive intravascular hemolysis, using a mouse model of phenylhydrazine (PHZ)-triggered erythrocyte destruction. We observed profound changes in mRNA levels for markers of tubular damage (Kim-1, NGAL) and regeneration (indirect marker of tubular injury, Ki-67), and tissue and vascular inflammation (IL-6, E-selectin, P-selectin, ICAM-1) in kidneys of PHZ-treated mice, associated with ultrastructural signs of tubular injury. Moreover, mass spectrometry revealed presence of markers of tubular damage in urine, including meprin-α, cytoskeletal keratins, α-1-antitrypsin, and α-1-microglobulin. Signs of renal injury and inflammation rapidly resolved and the renal function was preserved, despite major changes in metabolic parameters of PHZ-injected animals. Mechanistically, renal alterations were largely heme-independent, since injection of free heme could not reproduce them, and scavenging heme with hemopexin in PHZ-administered mice could not prevent them. Reduced overall health status of the mice suggested multiorgan involvement. We detected amylasemia and amylasuria, two markers of acute pancreatitis. We also provide detailed characterization of renal manifestations associated with acute intravascular hemolysis, which may be mediated by hemolysis-derived products upstream of heme release. This analysis provides a platform for further investigations of hemolytic diseases and associated renal injury and the evaluation of novel therapeutic strategies that target intravascular hemolysis

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

International audienceRhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies