Charles TRUILLET
BioMaps – U1281 – CEA – Université Paris Saclay – ORSAY
Gaëtane NOCTURNE
UMR-S 1184 IMVA – Hôpital de Bicêtre – KREMLIN-BICETRE
Sjögren’s disease (Sjo) is an autoimmune disease characterised by lymphocyte infiltration, leading to a dry syndrome. In 30% of patients, it leads to systemic involvement. Unfortunately, there is currently no validated treatment for Sjo’s disease. The disease is characterised by chronic activation of B lymphocytes, based on complex communication between epithelial cells, particularly those of the salivary glands (SGEC), and immune cells. It is crucial to develop preclinical models of the disease that integrate the epithelial cells and the immune compartment.
The advent of patient-derived organoids has revolutionised preclinical models in cancer. Organoids model the interactions between patient tissue and immune cells. These models make it possible to accurately predict the body’s response to immunotherapies, including side effects. They therefore represent a significant step towards personalised medicine in cancer treatment.
Our teams are working to develop immuno-organoids derived from patients’ salivary glands as new study models for Sjögren’s disease and as a screening platform for potential therapies. This project is at the interface between autoimmunity and cancer. We aim to optimise patient-derived organoids developed in the context of cancer and apply them to the field of autoimmunity. In turn, we will use these organoids to gain a better understanding of the side effects associated with immunotherapy.
David MICHONNEAU
Service d’Hématologie – Hopital Saint Louis – PARIS
Acquired Aplastic Anemia (AAA) is characterized by a bone marrow failure secondary to an abnormal T-cell immune response against hematopoietic stem cells, with treatment relying on the use of immunosuppressive drugs or allogeneic hematopoietic stem cell transplantation. One of the most severe complications is progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), affecting over 20% of patients. Upon diagnosis, nearly 30% of patients already present somatic mutations within hematopoietic stem cells (HSCs), and the risk of clonal evolution persists in patients treated with immunosuppressive drugs who have achieved complete response. The abnormally high frequency of these mutations, even in young patients, suggests they may also play a role in initiating an abnormal immune response against the hematopoietic stem cell. The objective of this study is to characterize the biological mechanisms contributing to the clonal evolution of AAA patients, and potentially identify new therapeutic targets. This project relies on the use of bone marrow samples from AAA patients, at diagnosis and during follow-up after immunosuppressive treatments. We will combine comprehensive mapping of immune cells and their transcriptomic profile with a study of clonal mutations of HSC, and their consequences on the transcriptomic profile and functional properties of HSCs. This work will enable us to better understand the relationship between HSC mutations and the abnormal immune response directed against these cells, and to identify the mechanisms leading to progression to malignant hematopathy.
Marianne BURBAGE
U932 Immunité et Cancer – Institut Curie -PARIS
Defining what makes cancer cells visible for the immune system is a key question to improve immunotherapeutic protocols. The immune system can detect fragments of intracellular proteins (called antigens) that are exposed on cell membranes. Specialized immune cells, called T lymphocytes, recognize such motifs at the cell surface and react only to those they identify as “abnormal”.
Classically, scientists have focused on antigens deriving from mutations that tumor cells accumulate. However, we have recently learnt that in cancer cells, some T lymphocytes recognize antigens that derive from regions of the genome that are not typically expressed (“dark”) but that “awaken” during oncogenesis. While they are promising target, “dark” antigens are poorly defined from an immunological perspective. It is for example critical to determine to what extent “dark” antigens are considered part of the immune “self”. Indeed, the immune system is “educated” to prevent recognition of “normal” antigens that could result in auto-immunity. This education takes place in an organ called thymus. The project we proposed aims at defining the expression of “dark” antigens in the thymic cells that educate the immune system. The data generated in this project will constitute a useful resource for the scientific community and will be instrumental to instruct the selection of targets to improve immunotherapies and anti-tumor vaccination.
Olivier BERNARD
INSERM U1170 – Gustave Roussy – VILLEJUIF
Our immune system is made up of different cell types, including B cells, which play a crucial role in adaptive immunity. These atypical CD11c+ B cells (ABCs) are linked to immune responses triggered by vaccinations, infections and autoimmune diseases, in both mice and humans. Recent studies indicate that they are a step towards the development of lymphomas such as Waldenström’s macroglobulinemia (WM). Through analysis of models and patient samples, we will identify the intrinsic and extrinsic mechanisms that lead to the progression and aggressiveness of WM, and their relations with ABCs.
Eric TARTOUR
INSERM U970 – Centre de recherche PARCC (HEGP) – PARIS
Immunotherapy (IO) is based on the stimulation of immune cells against cancer. There are situations where these immune cells are resistant to this activation. In this project, we aim to validate a new resistance mechanism based on an interaction between the CD70 molecule expressed by tumor cells and the CD27 molecule present on certain immune cells. In addition, the CD27 molecule can be measured in plasma (sCD27). High sCD27 values may predict resistance to some forms of IO but not others in kidney cancer and melanoma patients. We will evaluate in this study the role of sCD27 biomarker in different types of current IO treatment to better guide and personalize possible therapeutic options in kidney cancer and melanoma patients.
Sophie LOTERSZTAJN
UMR 1149 – Université Paris Cité Faculté de Médecine – Site Bichat – PARIS
Chronic liver diseases are marked by a high burden due to the occurrence of fibrosis its end-stage cirrhosis, and hepatocellular carcinoma (HCC). They constitute a major public health problem with high mortality, 2/3 of which is linked to liver cancer, which makes cirrhosis a precancerous condition. Chronic inflammation plays a major role in the progression of the disease and constitutes a privileged target for reducing fibrosis and preventing cancer. Clonal hematopoiesis or “CHIP” is the presence of one or more mutations in blood cells, which can lead to hematological cancer and expose one to an increased risk of chronic inflammatory diseases. Our project aims to establish the relationship between CHIP, cirrhosis and progression to liver cancer, as well as to define the common mechanisms involved.
Christel GOUDOT
U932 Immunité et Cancer – Institut Curie -PARIS
In recent decades, cancer vaccines have raised hopes, as they have been able to stimulate immune response against tumor antigens. Nevertheless, immunosuppression is major challenge. It is therefore essential to improve and broaden the repertoire of antigens for vaccines. Recently, new classes of tumor antigens have been discovered, such as transposable elements, as a broad source of tumor neo-peptides. Nevertheless, the immunogenicity of the latter remains an important issue to be addressed. We therefore propose to combine state-of-the-art artificial intelligence methods with experimental validation to characterize immunogenic peptides derived from these regions. This will open up promising new therapeutic perspectives in cancer immunotherapy.
Franck CARBONNEL
Service de Gastroentérologie – Hôpital Bicêtre -KREMLIN-BICÊTRE
Immune checkpoint inhibitors (ICI) are a major advance in the treatment of cancer. They facilitate the elimination of cancer cells by stimulating immune cells. Yet, the therapeutic effect of ICI is variable, even in patients with tumors sensitive to ICIs (melanoma, lung cancer, urinary tract cancer). The composition of the intestinal microbiota is associated with the efficacy and safety of ICI. ATHENA aims to describe the microbiota metabolites associated with response and toxicity of ICIs, and to understand their interaction with immunity within the tumor. This study extends 2 clinical studies completed by our group. The results will contribute to the development of probiotics, prebiotics and metabolites from gut bacteria, in order to improve the safety and efficacy of ICI.
Camille BIGENWALD
Immunologie des tumeurs et immunothérapie – Gustave Roussy – VILLEJUIF
CAR T cell therapy uses genetically modified T lymphocytes to target tumor cells. It is effective against B lymphomas, B leukemias and multiple myeloma resistant to more conventional treatments. Despite its efficacy, almost 40% of patients experience delayed hematological toxicity, persisting for more than 3 weeks after injection. This toxicity results in high morbidity, requiring transfusions and impacting quality of life. Initially attributed to the treatments previously administered to patients, we now know that it is linked to the injection of CAR T cells. The mechanism of this toxicity remains unknown, making its management non-standardized and necessitating in-depth study for its prevention and treatment.
Patricia LEPAGE
Micalis UMR 1319 – INRAE – JOUY-EN-JOSAS
Despite significant advances in cancer biology and crucial therapeutic innovations over the last decade, understanding individual trajectories in cancer treatment response remains an unreached goal. Metagenomics of the microbiome highlighted a link between our microbes, disease progression, and immunotherapy treatment response. While data-driven approaches have been developed to leverage the gut microbiome to ameliorate immunotherapy efficacy, the mechanisms underlying the interplay between the microbiome and treatment’s response are far from being resolved. The high inter-individual variability of the microbiome stands in the way of global therapeutic management. Yet, advances in microbial culturing technologies allow mimicking functional human-like microbiomes ex-vivo (microbiome avatars). Techniques such as fed-batch culturing reproduce nutritional and environmental conditions in bioreactors (also called anaerobic digesters or fermenters) and allow a longitudinal follow-up of microbial modifications/adaptations. The ambition of MelanoCult is to harness novel micro-fermentation technology (microfluidic-coupled micro-bioreactor) to develop personalized ex vivo microbiome avatars for patients with metastatic melanoma, in order to test and propose customized microbial modulation strategies to improve cancer response to immunotherapy.
Charles TRUILLET
BioMaps – U1281 – CEA – Université Paris Saclay – ORSAY
From targeted therapies to immunotherapies, including conjugated antibodies and vectorized radioimmunotherapies, antibodies play a pivotal role in cancer treatment, significantly extending patient survival and addressing aggressive cancers. However, only a subset of patients responds to these treatments, highlighting the need to identify predictive biomarkers for more precise patient selection and optimal treatment strategies. ImmunoPET medical imaging, which relies on the coupling of antibodies and radioisotopes, represents a significant advancement in patient care. A consortium from the University of Paris-Saclay leaded by the SHFJ is at the forefront of innovative research in ImmunoPET. A critical step in this project involves characterizing marked antibodies before and after radioligand injection using multidetector HPLC, UV, and radioactivity, forming the core of this funding proposal.
Françoise PORTEU
INSERM U1287 – Gustave Roussy – VILLEJUIF
Hematopoiesis is the physiological process by which all blood cells are produced. It resides mainly in the bone marrow, and begins with multipotent hematopoietic stem cells that differentiate into all hematopoietic lineages. During this differentiation, cells are characterized by a set of membrane markers known as cluster of differentiation. Hematopoiesis can be altered leading to myeloid or lymphoid hematological malignancies, which are the focus of INSERM U1287 and U1170. Our objectives are to understand their initiation and development, and to find curative treatments, notably by using multiparametric cytometry to assess the distribution of marrow and blood progenitors/precursors in normal and pathological contexts, before and after treatment, coupled with the cell cycle, activated signaling pathways and intracellular protein levels
Marie-Laure ARCANGELI
INSERM UMR1170 – Gustave Roussy – VILLEJUIF
Tumoral development is a multi-step process influenced by cell of origin of the oncogenic mutation as well as the way the different cancer cells respond to stress generated either by their microenvironment and/or therapies. Recent technics in genome manipulation and cell reprogramming (such as induced pluripotent stem cells, iPS) as well as the possibility to analyze single cells allow a better understanding in vitro of primary samples and the modeling of the transformation process. Therefore, the common approach of all the participants to this project is to design tumoral transformation models from primary cells, including ex-vivo analyses that will permit to better understand steps involved in oncogenesis and to set up functional screening for new therapeutical approaches. The realization of this project needs the acquisition of a performant microscope capable of automated analyses allowing for the analysis of multiple conditions.
Mehdi TOUAT
UMR S 1127 – Institut du Cerveau – PARIS
High-throughput imaging is a technique that enables automated optical microscopy and image analysis of large numbers of samples. Coupled with fluorescent markers, this technique allows the phenotypic analysis of cells of interest (e.g. tumor, immune) as well as the evaluation of their response to various perturbations (e.g. immunotherapy or genomic modification) in 2D cell culture or 3D organoid (in vitro cultures which show architecture and functions close to the ones of tissues from which they derive) models. Through this project, we will acquire a new microscope enabling high-throughput, high-resolution confocal microscopy imaging of live and fixed 2D cell cultures, tissues and organoid models. This will enable the detailed study of interactions between immune and tumor cells in new generation 3D models, the evaluation of new immunotherapy strategies, and the search for cellular or molecular mediators involved in dysimmune adverse reactions associated with cancer immunotherapies.
Samad MOHAMMADNEZHADDARYANI
INSERM U981 – Gustave Roussy – VILLEJUIF
This request is part of the MELAVATAR program, which aims to optimize the treatment of melanoma patients undergoing immunotherapy by developing algorithms that incorporate classical biomarkers obtained from tumor and blood samples of patients before and during treatment, as well as new markers developed in our laboratory, particularly concerning the metabolism of tumor and immune cells. These algorithms will be developed to address three main clinical objectives: 1) predicting the response to mono-immunotherapy with anti-PD1; 2) characterizing patients for whom treatment can be de-escalated (using a double immunotherapy injection instead of four); 3) predicting the occurrence of autoimmune-like side effects. The requested equipment will help optimize the isolation of relevant cell populations and quickly study their metabolic state ex-vivo.
Encarnita MARIOTTI-FERRANDIZ
UMRS959 – Immunologie – Immunopathologie – Immunothérapie – PARIS
Autoimmune and inflammatory disorders (AIDs) result from the body’s immune system attacking its own tissues and often arising as adverse events in cancer treatment with immune checkpoint inhibitors. There is a critical need for disease specific treatments and diagnostic markers. AIDs result from T and B lymphocytes losing self-tolerance to self-antigens. DeepAIRR proposes an innovative platform to explore AIDs through systems immunology approaches, focusing on single-cell and bulk sequencing of the T and B cell antigen specific receptors as well as their transcriptome. Leveraging the i3 lab expertise in AID research and omic data analysis, DeepAIRR aims to provide mechanistic insights into AID pathophysiology, potentially leading to new therapies and biomarkers, advancing patient care.
Julie HELFT
INSERM U1016, CNRS 8104 – Institut Cochin – PARIS
A simplified view of the tumor would be to think that this organ is composed of a cluster of cells that has accumulated genetic alterations leading to uncontrolled proliferation. However, it is now known that tumors are composed of a multitude of cell types within a complex microenvironment that promotes tumor growth and dissemination and influences the response to treatments. It is now possible to finely characterize the tumor microenvironment at the protein and transcriptomic level, thanks to new techniques of treatment of tumor tissue sections, in order to adapt immunotherapeutic treatments. The digitalization of these slides by a slide scanner is essential and will allow to analyze the complexity of the tumor microenvironment in a simple, fast and reproducible way.
Thomas MERCHER
INSERM U1170 – Gustave Roussy – VILLEJUIF
The genomic analyses carried out in recent years to characterize cancers have identifies genes that are mutated or whose expression is altered in tumor cells or in nearby cells like immune cells. In order to functionally validate these results and progress towards a clinical application of these observations, it is essential to quantify the expression and activation of the proteins encoded by these genes within the important cells of the tumors, which are often in limited supply for our analyses. In this project, we will use an equipment that requires a reduced number of cells to quantify protein expression and activation in different tumor
and immune cell subpopulations.
Cyril CATELAIN
INSERM UMR1170 – Gustave Roussy – VILLEJUIF
Understanding tumorigenesis processes requires the characterization of cells from patient samples. Flow cytometry is the most suitable technique because it allows a varied number of biological parameters to be examined. The CONCERTO project brings together 6 research teams on the Gustave Roussy site whose goal is to find new therapies for the benefit of the patient, either by characterizing all the cells collected during a biopsy (diseased cells and healthy cells), either by developing mouse models to assess the impact of “healthy” immune cells on the tumor, or by developing models to understand the process of cancerous transformation.
Aurélien MARABELLE
INSERM U1015 – CIC1428 – Gustave Roussy – VILLEJUIF
The PORTRAIT SPECTRAL project is dedicated to predicting and personalizing anti-tumor immunotherapies by analyzing fresh tissues (tumor biopsies and whole blood). The immunological portrait of each patient and their cancer is then used to guide these patients into appropriate therapeutic cohorts. The ITAC DIM has funded the acquisition of a technology that doubles the number of parameters analyzed on fresh tissues. This will allow for a more detailed analysis of the immunology of patients and their cancer, leading to the identification of new predictive biomarkers of efficacy and/or side effects and to propose new therapeutic options for patients with cancer.
Guy GOROCHOV
INSERM U1135 – CIMI-Paris – PARIS
Despite the progress in new anti-tumor immunotherapies that have dramatically improved the prognosis of many cancers, malignant brain tumors of the glioma type remain largely insensitive to these new approaches. Neither the treatments with antibodies capable of reactivating anti-tumor immunity, nor the new cellular therapies have been able to improve patient outcomes and their survival prognosis remains bleak. We will take advantage of rare situations where these brain tumors are infiltrated by B lymphocytes secreting antibodies of unknown specificity. We postulate that some of these antibodies will allow us to define the targets recognized in tumors. Moreover, such antibodies could be manufactured quickly and on a large scale for a therapeutic purpose and used in injectable form or grafted on killer lymphocytes to guide the latter towards the tumor. Strangely enough, another type of B cell, different from the one mentioned above, also infiltrate tumors but is associated with poor cancer prognosis. We shall also study those cells.
Makoto MIYARA
Plateforme de cytométrie AP-HP Sorbonne Université – Hôpital de la Pitié-Salpêtrière – PARIS
We aim to strengthen our flow cytometry platform within the Immunology Department at Pitié-Salpêtrière. Our ultimate goal is to improve the standard of care of patients with autoimmune diseases and those treated with immunotherapies: through more detailed and holistic analyses, we can enable our clinical colleagues to provide more accurate diagnosis, better monitoring, and thus, improved overall patient care.
Our platform encompasses two development projects in biological immunology linked to the acquisition of the FACSDiscover S8, exploring two key dimensions of patient care: diagnosis and prediction of the effectiveness of immunotherapies.
Roberto MALLONE – François BATTEUX
INSERM U1016 – Institut Cochin -PARIS
The incidence of type 1 diabetes (T1D) continues to rise, particularly in children. This autoimmune disease completely destroys pancreatic β cells and requires lifelong insulin treatment. It is possible to detect the autoimmune attack by measuring autoantibodies before this destruction, and thus delay it, particularly in relatives of patients who are more at risk. Such screening requires a simple, high-throughput assay, ideally on samples collected all over France, outside specialized hospitals. The aim of this project is to acquire an automated assay system to develop a pilot project for the early diagnosis and management of T1D, by measuring autoantibodies on blood drops self-collected by finger prick at home and sent by mail.
Valentine FERRE
INSERM IAME UMR1137 – Service de Virologie – Hôpital Bichat – Claude Bernard – PARIS
Screening for precancerous lesions of the cervix and anus is based on the detection of papillomavirus (HPV), which is a highly sensitive technique, but HPV infections are frequent and the development of markers to identify which lesions are most at risk of progression to cancer is crucial. HPV infection can induce aberrant methylation patterns in the cell genome, which are involved in carcinogenesis. Methylation quantification could enable to prevent overtreatment of lesions that are not going to progress while patients with the most high-risk lesions could be treated in priority. The aim of the MetAna project is to automatized methylation quantification, which is currently manual and very cumbersome, to make it accessible and usable in large-scale screening for ano-genital HPV-induced cancers.
Myriam MORCEL
Fédérations Hospitalo–Universitaires FHUs (DRCI) – KREMLIN-BICÊTRE
The Workshop Women in Science-Medecine or ‘WiS’ is a workshop organised by the Federations Hospitalo-Universitaires (FHUs). Lasting half a day, the WiS workshop aims to inspire participants and give them the means to take action in their personal and professional lives.
David KLATZMANN
UMRS959 – Laboratoire Immunologie Immunopathologie Immunotherapie – KREMLIN-BICÊTRE
Regulatory T cells (Tregs) are important therapeutic targets for many immunopathologies. Stimulating Tregs with interleukin-2 (IL-2), the key cytokine supporting Treg fitness, is being actively developed. IL-2 is very well tolerated and activates regulatory T cells, inducing a therapeutic effect in several autoimmune diseases. We have been the pioneers for this therapy which is now widely investigated by many academic researchers and companies. In order to foster interactions in the field, we have initiated a very unique international conference entirely dedicated to the biology and therapeutic use of IL-2 in autoimmune diseases, inflammatory diseases, allergy, Treg cell therapy, transplantation and cancer.
Marc SANSON
Siric CURAMUS – Institut du Cerveau – PARIS
Primary brain tumors are among the most resistant cancers to immunotherapy due to the composition and specific organization of the microenvironment, ie the noncancerous cells present within the tumor that interact with tumor cells to constitute the tumor. Recent major advances in understanding these interactions and complex organization, offer real therapeutic hopes. To report on this, we have brought together a panel of top scientists in the field, while also giving ample space to works carried out by junior researchers. This event will be open to researchers, clinicians, students, as well as patient partners of the CURAMUS SiRIC, organizer of the meeting. We hope to foster new collaborations to identify new therapeutic avenues, generate interest, attract young researchers, and disseminate information to patients and the public.
François-Xavier DANLOS
INSERM CIC1428 – Gustave Roussy – VILLEJUIF
The iTox symposium is an annual event designed to bring together experts on immune related adverse events of cancer treatments. It aims to educate students and doctors, enhance knowledge on immunotherapies, and encourage interdisciplinary exchanges to initiate collaborations. Each session expands the discussion to new immunotherapies, including this year bispecific T cell engager treatments and cell therapies beside to immune checkpoint blockade antibodies. The goals are to improve the management of side effects and to stimulate innovation in patients with cancer care.
