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Inflammation, complement and cancer

Inflammation and complement overactivation are hallmarks of a variety of life-threatening diseases including cancer and renal dysfunctions. The missions of the team are:

 1) To decipher the molecular and cellular mechanisms of the complex interplay between the tumor and its immune microenvironment and how these interactions are modulated by external microbial stimuli. By using high-throughput bioinformatics combined with genomic analyses, cellular approaches and in situ analyses we will dissect how tumor cells through genetic and epigenetic modifications and through complement activation, shape the anti-tumor immune response, with a particular focus on lung and renal cancer. In the era of precision medicine, we will compare the response to immunotherapy of groups of patients, stratified on the molecular characteristics of their tumors. We will search for novel prognostic and theranostic biomarkers in large cohorts of patients, available in the laboratory, thanks to strong interactions with clinicians. We will use animal and cellular models to gain fundamental knowledge on the interaction of tumor cells with their environment, including viruses and bacteria, which will allow us to identify novel therapeutic targets, especially among the pattern recognition receptors and complement proteins.

2) To understand how inflammation and complement overactivation contribute to the pathogenesis of rare renal diseases. We will focus on fundamental and translational research linking complement to pathogenesis of renal chronic inflammatory and thrombotic diseases, for which we hold among the largest cohorts in the world. We will study the mechanisms of renal injury using in vitro and in vivo models and we will search for novel therapeutic targets and molecules. Identification of new diagnostic and prognostic markers for complement-mediated diseases will help to improve the strategies or patients’ management.

The team is divided in three distinct groups:

Inflammation and cancer group (Pr. Cremer, Pr. Damotte, Pr. Wislez, Pr. Leroy, Dr. Joubert, Dr. Sibéril) – Local and systemic inflammation are known to influence tumor behavior. The tumor immune environment has a strong prognostic value suggesting its role in the disease control, but is highly heterogeneous among patients. Origin of such heterogeneity is not fully understood but it could be driven by carcinogen exposure (tobacco, pollution), viral or bacterial infections, host immune system and tumor cell characteristics. We will investigate the role of the fitness of the patient and its nutritional status, and the impact of infectious microbes and microbiota (including vurises), on metabolic reprogramming, inflammation and on the tumor microenvironment with a particular focus on immune responses. These questions are mainly addressed in non-small cell lung carcinoma (NSCLC, including multiple tumor bearing patients) and in murine models of lung tumors.

Immunotherapy and cancer group (Pr Sautès-Fridman, Pr Fridman, Dr. Vano, Dr. Sun) – Our goal is to identify biomarkers of response to immunotherapies in the tumor microenvironment, with a major emphasis on renal cell carcinoma (RCC) where we previously identified molecular and phenotypic signatures associated with high risk of relapse and on soft tissue sarcoma where we recently identified an immune rich class associated with clinical outcome and response to immunotherapy. Only a fraction of cancer patients respond to immunotherapies. We participate to several randomized clinical trials that use transcriptomic or in situ biomarkers of the TME to select the metastatic cancer patients before treatment, in order to validate our hypotheses and enrich patients response to immunotherapies.

Complement and diseases group – There is a rise of interest towards complement due to the emergence of complement-targeting therapeutics and the discovery of its roles in diseases, considered complement-unrelated.

• Axis 1: Complement as modulator of cancer microenvironment (Dr. Roumenina). Increasing evidences suggest that complement is a major, previously underestimated, modulator of cells behavior. We study complement as a modulator of the tumor cell fate and tumor microenvironment. Gained fundamental knowledge will allow us to search for novel prognostic markers in patients’ cohorts with renal and lung cancers.

• Axis 2: Complement in translational medicine (Dr. Fremeaux-Bacchi, Dr Dragon –Durey, Dr. Roumenina). In this axis we study complement as driver of tissue injury: We aim to understand the mechanisms of complement mediated tissue injury in rare kidney diseases (atypical hemolytic uremic syndrome, C3 glomerulopathies, lupus nephritis), in sickle cell disease and in inflammatory myopathies, using in vitro and mouse models as well as cohorts’ studies. We test novel therapeutic molecules developed in the team or provided by companies. Our work has a major societal impact, thanks to transfer to diagnostics and patients’ management, through the Complement diagnostics laboratory of Dr. Fremeaux-Bacchi in HEGP hospital and the collaborating clinicians.
 


Healthy tissues as well as cancer cells can be challenged by microbial infections, pollution or tobacco and can undergo genetic modifications leading to mutations. In this context, inflammatory events and complement activation can occur, that impact both tumor and healthy tissue behaviors.
 Altogether, these events shape and modulate the immune contexture, meaning the immune cell subpopulation densities, their activation and exhaustion levels or their functions. A better and global understanding of how immune contexture is shaped in different pathologies will help to define better diagnostic, prognostic and theranostic biomarkers, as well as to define optimal therapeutic strategies.

 

 

 

Team Leader : Isabelle CREMER (PU; Sorbonne Univ).

Deputy director : Lubka ROUMENINA (CR; Inserm)



Team Members : 

Researchers: Marco ALIFANO (PU-PH; Univ Paris Descartes), Emelyne CAMELIN (PH; Univ Paris Descartes), Sophie CHAUVET (MCU-PH; AP-HP)Diane DAMOTTE (PU-PH; Univ Paris Descartes), Marie-Agnès DRAGON-DUREY (MCU-PH; Univ Paris Descartes), Véronique FREMEAUX-BACCHI (PH; AP-HP), Hervé FRIDMAN (PU-PH em; Univ Paris Descartes), Pierre-Emmanuel JOUBERT (MCU; Sorbonne Univ), Karen LEROY (PU-PH; Univ Paris Descartes), Audrey LUPO (MCU-PH; Sorbonne Univ), Jules RUSSICK (ATER; Sorbonne Univ), Catherine SAUTES-FRIDMAN (PU em: Univ Paris Descartes), Sophie SIBERIL (MCU; Sorbonne Univ), Cheng-Ming SUN (CR; Inserm), Marie WISLEZ (PU-PH, Univ Paris Descartes).

Technical Staff: Aurélie BONI (AI; CDD), Antoine BOUGOUIN (IE; CDD), Irelka COLINA MORENO (IE; CDD), Ilenia GIGLIOLI (IE; CDD), Nathalie JOSSEAUME (Tec; Sorbonne Univ), Nathalie-Tassadite JUPITER (Tec; Inserm), Guillaume LACROIX (AI; CDD), Laetitia LACROIX (IE; CDD), Solenne MARMIER (IE; Sorbonne Univ), Nathalie MATHIOT (AI; AP-HP), Victoria POILLERAT (IE, CDD), Tania RYBKINE (IE; Sorbonne Univ), Noémie SIMON (IR; CDD), Carine TORSET (IE; CDD), Yoan VELUT (IR; CDD).

Young Researchers: Mahmud ANGRINI (PhD student), Marie DAUGAN (PhD student), Maxime MEYLAN (PhD student), Aditi VARTHAMAN (Post-Doc).

Students:  Idris BOUDHABHAY (Master Student), Melchior CHABANNES (Master Student), Alice LE CLECH (Master Student), Lucas LEONARDI (Master Student),  Manon MARTINS (Master Student), Marco MOREIRA (Master Studen), Margot REVEL (Master Student), Hajar OUAHMI (Master Student).

Administration : Mehdi BENNACI, Esther PEROUMAL

Contact details : 01 44 27 91 00    Email: mehdi.bennaci@crc.jussieu.fr


Publications

  • Dajon M*, Kristina Iribarren K*, Petitprez F, Marmier S, Lupo A, Gillard M, Ouakrim H, Navas V, Di Bartolo V, Joubert PE, Kepp O, Kroemer G, Alifano A, Damotte D, Cremer I. Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells. *equal contribution. OncoImmunology. 2018. In press
  • Merle NS, Grunenwald A, Rajaratnam H, Gnemmi V, Frimat M, Figueres ML, Knockaert S, Bouzekri S, Charue D, Noe R, Robe-Rybkine T, Le-Hoang M, Brinkman N, Gentinetta T, Edler M, Petrillo S, Tolosano E, Miescher S, Le Jeune S, Houillier P, Chauvet S, Rabant M, Dimitrov JD, Fremeaux-Bacchi V, Blanc-Brude OP, Roumenina LT., Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles., JCI Insight. 2018;3(12). pii: 96910. doi: 10.1172/jci.insight.96910. PMID: 29925688
  • Biton J, Mansuet-Lupo A, Pécuchet N, Alifano M, Ouakrim H, Arrondeau J, Boudou-Rouquette P, Goldwasser F, Leroy K, Goc J, Wislez M, Germain C, Laurent-Puig P, Dieu-Nosjean MC, Cremer I, Herbst R, Blons H, Damotte D. TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma. Clin Cancer Res. 2018 May 15. doi: 10.1158/1078-0432.CCR-18-0163. PMID:29764856
  • Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, Cailliez M, Deschenes G, Fischbach M, Karras A, Nobili F, Pietrement C, Dragon-Durey MA, Fakhouri F, Roumenina LT, Fremeaux-Bacchi V. C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.; Kidney Int. 2017;92(5):1232-1241. PMID: 28712854
  • Calderaro J, Petitprez F, Becht E, Laurent A, Hirsch TZ, Rousseau B, Luciani A, Amaddeo G, Derman J, Charpy C, Zucman-Rossi J, Wolf Herman Fridman W, Sautès-Fridman C. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 2018 Sep 11. pii: S0168-8278(18)32373-0. doi: 10.1016/j.jhep.2018.09.003. PMID: 30213589

 

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