HLA-G: a new target for the addressing of anti-tumor therapies
The main objective of this project is to demonstrate that the HLA-G molecule can be used to target treatments against a variety of tumors, particularly those lacking specific tumor antigens (TSA).
Project Rationale: HLA-G has two key characteristics that make it attractive for antitumor therapy:
Immunosuppressive function: HLA-G acts as an immune checkpoint, blocking cytotoxic immune cells that are anti-tumor, thereby allowing tumor cells to evade immune surveillance.
Selective expression: HLA-G is primarily a fetal molecule, with virtually no expression in adults. However, it is commonly re-expressed in many solid tumors.
The restricted expression of HLA-G in pathological tissues, mainly tumor cells, makes it an appealing target for therapeutic targeting. This characteristic will be exploited in the project. Indeed, a molecule that is specifically expressed by a tumor is an ideal TSA, enabling targeted treatment with minimal side effects on healthy cells. Unfortunately, tumor-specific antigens are rare, costly to develop, and, for most tumors, none exist to date.
HLA-G, expressed in the majority of tumor types—both common and rare—represents an excellent candidate for a multi-tumor TSA.
Project Methodology
The project will use microfluidic chips and 3D tumor avatars (tumor spheroids derived from patients with renal cancer) already established in the laboratory to evaluate the efficacy of BiTEs (Bi-Specific T-cell Engagers). One side of the BiTEs will target HLA-G as the addressing molecule, and the other side will target tumor-infiltrating cytotoxic cell antigens (T lymphocytes and NK cells).
Resources and Expertise
The project will build on the laboratory’s expertise in:
The HLA-G molecule and its functions in immunology and immuno-oncology, a subject the laboratory has studied for over 20 years.
The immune environment of renal tumors, particularly intratumoral cytotoxic cells.
Clinical expertise in immuno-urology-oncology from clinicians at St. Louis Hospital, Paris.
The project will employ advanced technologies, including spectral flow cytometry and 3D tumor avatars in microfluidic chips.
Conclusion
By using innovative technologies and relying on strong expertise, the project aims to develop new therapeutic strategies applicable to a broad range of cancers expressing HLA-G.
Crosstalk between adipocytes and T lymphocytes, key players in immunity in adipose tissue
The metabolic and endocrine role of adipose tissue (AT) is established. The AT is composed mainly of adipocytes but also of immune cells, best known for controlling the metabolic homeostasis of the tissue. The immune activity of TA is associated with the secretion of cytokines and metabolites that modulate its immune function. Obesity, characterized by an accumulation of AT at the subcutaneous or visceral level, is associated with the local inflammation of AT. However, the AT can be infected by different pathogens and it constitutes a site of accumulation of CD8 T lymphocytes (TL) specific for them, which protect against reinfection. These data therefore encourage us to investigate the interactions between adipocytes and CD8-TL in the AT.
The project will be carried out in the CoVir team, which is developing various projects aimed at deciphering the anti-infectious properties of adipose tissue. It is part of a consortium established for an ANR project (INSERM, CNRS, Institut Pasteur de Lille). The objective of the team's project is to study the local contribution of adipocytes and CD8-TL residing in the TA during influenza virus infection in a non-human primate (NHP) model. The NHP presents metabolic and immune responses similar to humans. In addition to in-vivo approaches in NHP, we will develop a 3D co-culture model to target the interaction between adipocytes and CD8-TL, without interference from inflammatory and metabolic signals external to TA. This project benefits from the historical expertise developed in the institute (IMVA-HB UMR 1184/I IDMIT, directed by R. Le Grand) concerning the study of viral infections in the preclinical model of PNH. IDMIT platforms provide equipment and expertise in histology, cytometry (LFC), cytokine/chemokine detection (L2I) and animal welfare (ASW).
The thesis project will focus on in vitro approaches. We will compare the interactions between adipocytes and LT, by studying the metabolic and immune response of each of these fractions. Indeed, adipocyte cells exhibit strong metabolic activity but exert their own immune activity (through the production of microbicidal peptides) and immunomodulatory activity. Concerning immune cells, their functional activity is dependent on their metabolic functions and it is crucial to evaluate the immune-metabolic modifications of immune cells in the presence of adipocytes. The organoid model will allow us to evaluate : (i) the impact of the context of obesity to those in a context of metabolic normality, (ii) the impact of viral pathogens on each of these two fractions. In the medium term, this model will make it possible to test strategies for modulating TA functions during metabolic pathologies or viral infections.
Complex brain organoid model reproducing the glioblastoma tumor niche and its immune component for the development of personalized medicine
Glioblastoma, responsible for 3,500 annual deaths in France, is an extremely aggressive brain tumor that is resistant to current treatments. Clinical trials in immunotherapy have shown only transient effects, underscoring the importance of understanding resistance mechanisms and developing more targeted therapeutic strategies.
We have developed an innovative model of glioma stem cell invasion in immunocompetent and vascularized brain organoids derived from induced pluripotent stem cells (iPSCs) (Raguin et al., submitted). This model faithfully reproduces the glioblastoma tumor niche, including vascular co-option, reprogramming of microglia into tumor-associated macrophages, and tumor recurrence following radiotherapy.
The aim of this PhD project is to derive a universal brain organoid model for the transfer of glioma cells from patients and lymphocytes to optimize the immunotherapy approach (CAR-T cells).
The project involves creating a universal model of human brain organoids that are immunologically "silent" by suppressing the expression of the HLA class I/II system in iPSCs (CRISPR/CAS9 for the ß2M and CIITA genes). Additionally, it aims to elucidate the mechanisms of immunosuppression induced by irradiation, such as the reprogramming of microglial/macrophage cells and the involvement of senescence. Various approaches to make the tumor microenvironment more conducive to immunotherapy will be explored, including activating the type I interferon pathway through genetic modification or with cGAS/STING pathway agonists. Subsequently, the use of CAR-T cells targeting an antigen overexpressed by glioblastoma cells (CD276/B7-H3) will be studied. This model could be used in personalized medicine by co-cultivating patients' tumor cells, monocytes, and CAR-T cells.
This project offers innovative perspectives for the personalized treatment of glioblastoma via immunotherapy and could represent a major advancement in this therapeutic approach.
Multiplexed whole-body in vivo imaging monitoring of pathogen dissemination and immune responses dynamics in tuberculosis
This thesis is dedicated to set up a multiplexed medical imaging monitoring of pathogen colonization and associated immune responses dynamics at the whole body scale for various infectious diseases. This could provide an innovative and non-invasive tool to better understand dynamics links between immune responses and pathogen distribution throughout the body and potentially provide new biomarkers associated to several diseases. To tackle this issue this thesis would implement such strategy in tuberculosis disease. The main aim is to determine the relationship between Mycobacterium tuberculosis dissemination and associated immune responses across the whole body during the course of tuberculosis infection from early infection to latent or active tuberculosis thanks to innovative multiplexed imaging protocols. The goal of this study is to provide correlations in time and space between local bacterial burden and several immune cell infiltrations (activated macrophages and T lymphocytes subsets) occurring following infection and detected over time by imaging. These findings could then provide, with minimal invasiveness, predictive biomarkers on disease or local granuloma progression and may provide also valuable insight on potential immune targets for future preventive or curative strategies based on modulation of the immune system. To do so, this thesis would take advantage of the preclinical Non-human primate model of tuberculosis developed in France and on our in vivo imaging of pathogens and immune cells expertise in NHPs. Of note, deeper immune cell profiling in samples of interest (imaging guided) will be assessed by spatial or single-cell transcripomic technologies in tissue samples to provide additional readouts on TB pathophysiology and potential treatment efficacy.