Team 9: (JJ Fournié): to improve the therapeutic strategies for lymphomas
Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are two of the most common hematopoietic diseases. They both share proliferation and microenvironmental dependence of tumour cells in secondary lymphoid organs, involvement of B cell receptor (BCR) signaling and anti-apoptotic pathways, and finally, immuno-chemotherapeutic treatments which improved survival. Despite a clear benefit of these new treatments, patients become refractory, invariably relapse and die. Emergence of immuno-chemo-resistant cells reflects several issues. These include intrinsic genomic alterations, cellular selection, interactions with Nurse Like Cells (NLC) of the microenvironment, lack of drugs- and/or antibodies- biodisponibility at the tumor site (lymph nodes), defective immune effector cells (Υδ T, CD8, NK) allowing immune escape. Indeed, the recently characterized landscape of genomic alterations in human lymphomas has unveiled the genes and signal transduction pathways which are recurrently altered in these diseases. Beyond suggesting new targets and drug candidates, this information also pinpointed immune escape mechanisms leading to emerging therapeutic approaches. As an example, anti-CTLA4 ipilimumab, anti-PD1 nivolumab, anti-KIR lirilumab and other antibodies can restore the cytolytic immune defenses harnessed by current immunotherapies of lymphomas. But whether combining such novel targeted immunotherapeutics and currently used chemotherapies will synergize or rather antagonize is still unclear, and might actually depend on the type of lymphoma, the patient's genetics and his immunity.
Our team focusses on this global issue by addressing the following researches:
- What new technology could detect low amounts of lymphoma cells?
- What are the main processes underlying relapse of aggressive NHL?
- SP cells and CLL /NLC cell interactions contribute to emergence and relapse of CLL. How to destroy these specific targets?
- Lymphomas often combine deep alterations of epigenetic regulation and strong capacity to immunoescape; could new epigenetic drug candidates reduce this immunoescape?
- Harnessing human Υδ T and NK cells against cancer is limited by their progressive exhaustion: how to avoid it?
In these studies, we apply different methodologies and assess new drug candidates such as:
- biomolecules and natural substances stimulating NK and Υδ T cells
- Small chemical inhibitors targeting lymphomas
- Monoclonal antibodies targeting microenvironmental support of NHL and CLL
These molecules alone and in associations are explored in vitro cultures in 2D and 3D (MALC) models of NHL cell lines, as well as in primary cells from patients. We also develop primary cells xenografts in murine models (NSG or SCID Beige). Altogether, theses studies should build a better understanding of the diseases, define new sensitivity/resistance criteria, and propose new immuno-therapeutic combinations for NHL and CLL.
Work from our team is supported by French and UE institutions and by LabEx TOUCAN, PHUC CAPTOR, Institut Carnot Lymphome (CALYM), INCa, ANR, charities and pharmaceutical partners.
Jean-Jacques Fournié's team is part of Labex TOUCAN & PHUC CAPTOR