Thesis director and contact person: André Herbelin
Keywords : Innate T lymphocytes, immunosurveillance, multiple myeloma, tumoral niche.
Start date: 10/02/2023
Our research team is dedicated to the control and monitoring of tumors by the so-called “natural” immune system represented by cells named innate T cells (ITC). We have described a new ITC subpopulation, the CD8 ITC, which we assume plays an important role in anti-tumor immunosurveillance, like the other ITC.
The main objective of the thesis proposal is the description of ITC, especially CD8 ITC, in the medullary tumor niche of multiple myeloma (MM) at different stages of the disease. We will study ITC/CD8 ITC phenotypically, as well as their innate function of IFN-γ secretion after TCR-independent stimulation.
This thesis proposal, by providing new knowledge on the modes of action of the immune system in MM, could ultimately contribute to the identification of immune markers predicting a complete and sustained clinical response in MM.
MM is an incurable malignancy characterized by the clonal proliferation of plasma cells (Pc) in the bone marrow (BM). Despite recent therapeutic advances, particularly the use of immunotherapy, the remission phases of MM remain transient.
To date, few studies exist on the control of MM by the immune system. Among them, the work of the team of L. Martinet, in humans and in mouse models, suggests that LT-αβ CD8 cells play a key role in the censorship of MM Pc. Indeed, these cells undergo an exhaustion/immunosubversion dependent on TIGIT and IL-18. This work led us to study in MM the CD8 ITC that we had identified in humans, which possesses anti-tumoral properties.
Our main hypothesis is that particular signatures of ITC/CD8 ITC reflect functioning of the tumor niche in close connection with progression, escape, or control of MM.
In MM, our preliminary data together with those of the literature show alterations of the ITCL/CD8 ITC compartment in peripheral blood during the course of the disease. In patients diagnosed with MM, we showed a higher frequency of CD8 ITC in peripheral blood, which was associated with a signature of exhaustion, and an innate function defect.
The thesis research aim is to clarify the mechanisms of involvement of these cells in the medullary niche of MM. For this purpose, we will study the frequency and functional status of ITC, including CD8 ITC. Specifically, we will define the place of CD8 ITC in the continuous gradient called “innateness”, going from CD4/CD8 adaptive T cells to NK cells. We will focus on efficacy, longevity, and plasticity (or “stemness”) of each of the populations of conventional T cells and ITC/CD8 ITC during the evolution of MM.
The main objective of the research thesis proposal will be to analyze the frequency and functional status of ITC, especially CD8 ITC, in the CD138(-) non-tumor hematopoietic BM fraction, by confronting patients at diagnosis or at relapse of MM to healthy subjects. To analyze the link between ITC status and disease progression, patients at diagnosis will be compared to patients in remission. Quantitative and functional analysis (after stimulation by the pro-inflammatory cytokines IL-12 and IL-18) of ITC will be combined with analysis of the main cellular compartments of innate (NK ) and adaptive (CD4 and conventional CD8 ) immune cells.
The main method used will be spectral flow cytometry allowing analyzes with more than 30 parameters on a single cell. The analysis methods will use both specific algorithms and classical manual analysis.
Master 2 with theoretical training in cellular immunology.
Knowledge of flow cytometry will be appreciated.