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Common pathways involved in Autoimmune Diseases, Cancer and Inflammatory Diseases (WP1)

Adaptive and innate immunity. The balance between pro vs anti-inflammatory immune cells (macrophages, T cells, dendritic cells) is opposed in C vs AID/ID.

WP1 Leader : Laurence Zitvogel

  • Rheumatoid arthritis (RA) and Sjögren’s syndrome (SS) are clonal B-cell proliferations. Xavier Mariette’s team has been working for years on B cells in these two systemic AIDs. The team has demonstrated the role of the BAFF cytokine as B-cell stimulator, the importance of the rheumatoid factor (RF)-B cells that could become clonal and transform into B-cell lymphoma and the effect of rituximab (RTX), a B-cell targeted therapy, in both diseases. Nevertheless, in both diseases, RTX is not able to cure the disease. It might be due to the fact that the pathogenic B cells represent a very small subset of B cells possibly organized as an oligo or monoclonal subset just like cancer cells. Team has preliminary results suggesting that these B cells overexpress CD47 (a “do not eat me” receptor) explaining their resistance to apoptosis induced by RTX. In this task, we explore the clonality of auto-immune B-cells in two mouse models (one of RA: K/BXN and one of SS: BAFF transgenic) as well as in RA and SS patients followed in our national reference center for rare systemic auto-immune diseases.
  • Follicular T helper cells (TFH) and peripheral T helper cells (TPH) are subsets of T cells involved in B-cell activation both in AID/ID and in cancer. Xavier Mariette’s team has data demonstrating the involvement of these 2 cell-subsets for activating B cells in SS. In cancer, TFH invade tumor beds, playing a beneficial role in breast and colon cancers (Gu-Trantien 2013, Bindea 2013). Distinct immunogenic commensals elicit TFH responses and humoral immunity that activate TH1 functions (Barton, Science 2019). Laurence Zitvogel and Roger Le Grand monitor ileal immunoscore, ileal microbiome, systemic IgA/G responses against commensals and PD1high TFH in tumors, lamina propria and blood in colon cancers in the setting of IBD or non-inflammatory colon cancers in animal models and in patients.

  • Monocytes heterogeneity and the balance between pro-inflammatory and anti-inflammatory macrophages in cancer and in AID/ID. In cancer, Franck Carbonnel has described heterogeneity of monocytes in some blood cancer. Jean-Luc Perfettinihas demonstrated that tumor associated macrophages (TAM) had an anti-inflammatory phenotype that could impair their anti-cancer activity. On the other hand, Xavier Mariette has recently demonstrated that in RA, there was an increased expression of mTNF on monocytes and a defect of polarization of blood monocytes into anti-inflammatory macrophages, due to an increase of miR155 (Audrey Paoletti, JI in press). In this task, the elements (micro RNA, alkylating drugs, radiotherapy, etc…) responsible for the differentiation into pro or anti-inflammatory macrophages and their metabolic reprogramming Angelo Paci studied in both types of diseases. Based on these observations, some therapeutic trials are initiated using antagomiRs. We use new technologies developed by Elias Fattalusing addressed liposomes specifically phagocyted by macrophages.
  • Dendritic cells and other myeloid cells in AID/ID and cancer. Maria-Antonietta d’Agostinohas demonstrated a critical involvement of DCs dysfunction in the development of spondyloarthritis, that are studied at the level of transcription factors with the aim of restoring immunological tolerance. Olivier Lambottehas developed antibodies against innate immune checkpoints modulating the functions of dendritic cells (anti-LILRs). Agonist and antagonist anti-LILRs are tested both in cancer and AID models. Roger Le Grand is investigating which DC subsets from the lamina propria can cross-present self-antigens from ileal apoptotic crypts in settings of immunogenic chemotherapy+/- ICB to deconvolute the frontiers between tolerance and immunity in cancer colons and IBD.
  • Neutrophils, NETs in AID/ID and cancer. Benjamin Besse and Roger Le Grand have shown that the neutrophil / lymphocyte ratio was associated with worse outcomes in patients treated with ICI, but not with chemotherapy. Neutrophils are associated with inflammatory process in NSCLC patients and resistance to ICI. Sylvie Chollet-Martin demonstrated that Neutrophils Extracellular Traps (NETs) released by activated neutrophils contain potent auto-antigens in AID. In this task Roger Le Grand and Sylvie Chollet-Martin perform a deep neutrophil characterization in advanced NSCLC patients before and after ICI treatment. The main goal of this research is to understand the potential common and opposite mechanisms by which neutrophils and NETS can promote autoimmunity and cancer.

Comparison of microbiota composition and functions associated with IBD and involved in response/toxicity to ICI in cancer patients is realized. PREMIS is a prospective translational study allowing to identify predictive markers of irAEs during cancer therapy with ICI partners Franck Carbonnel, Caroline Robert, Laurence Zitvogel, Nathalie Chaput-Gras, Angelo Paci and Patricia Lepage.
Meta-omics (amplicons sequencing, shotgun sequencing, metabolomics) and culturomics analyses of stools (Patricia Lepage, INRA) combined with humoral and cellular memory responses to distinct commensals allows to identify ecosystems associated with irAEs, objective responses or hyperprogression. The data from such outliers are informative and provide insights into pathophysiology of AID, providing hypotheses to be tested in animal models by Laurence Zitvogel. Angelo Paci explore the role of short chain fatty acids produced by the gut microbiota in cancer response and ICI toxicity.

  • If there is a very minor subset of clonal cells responsible of AID or specific abnormalities of macrophages leading to modified anti-inflammatory activity, it is crucial to detect in vivo these minor subsets. For this task, we take the opportunity to have in the consortium the IDMIT research infrastructure platform (Roger Le Grand) at Fontenay aux Roses, which combines macaque facility, mass spectrometry and advanced technics for animals imaging like TEP-CT. On this model, Roger Le Grand and Salima Hacein-Bey create a platform with advanced technologies for human immune monitoring at Bicêtre in a new research building dedicated to translational medicine opening in 2021.
  • Dominique Lamarque found that gastric inflammation can be detected by specific changes in reflectance spectra from 420 to 1000 nanometers. We study the reflectance spectra in inflammatory colitis in human and animal models.

Timetable, deliverables and other proposed indicators

  • D1.1.1: Expansion of CD47+ B cells in RA and in SS (animal models and human disease)
  • D1.1.2: Proof of concept in animal models that anti-CD20 + anti-CD47 is more efficient than anti-CD20 in RA
  • D1.1.3: Abnormal expansions of TFH and TPH in SS
  • D1.1.4: Abnormalities of TFH and TPH in colon cancer, link with associated inflammation
  • D1.1.5: Relations between TFH, TPH in colon cancer, microbiota and response to ICI

  • D1.2.1: Relations between monocytes heterogeneity and autoimmunity in myeloid leukemias
  • D1.2.2: Proof of concept of a new target for activating pro-inflammatory macrophages in cancer
  • D1.2.3: Proof of concept of a new target for activating anti-inflammatory macrophages in RA
  • D1.2.4: Discovery of new LILR inhibitors and activators for modulating macrophages and DCs functions
  • D1.2.5: Proof of concept in animal models that targeting DC subsets can deconvolute the frontiers between tolerance and immunity in cancer colons and IBD
  • D1.2.6: Comparison of neutrophil characterization in patients with lung cancer and AID/ID
  • D1.2.7: Creation of the human immune monitoring platform in the Bicêtre translational medicine building

  • D1.3.1: Comparison of microbiota associated with IBD and response/toxicity to ICI in cancer patients
  • D1.3.2: Correlation between microbiome, immune response to commensals and response to ICI
  • D1.2.3: Animal models based on outliers to demonstrate the link between microbiota, cross-reactive immune response and response/toxicity to ICI