CV Science

Nathalie Rouas-Freiss PharmD and PhD Immunology

Course and current status

Professional Situation: Researcher at the Commissariat à l’Energie Atomique-Head, Immunology Laboratory, Hemato-Immunology Research Department

Scientific Experience

1989-1993 Master and Ph.D. of Science in Immunology, University of Paris VII, France

1993-1995 Post-doctoral Research Fellow, INSERM U255 – Dr Fridman, Curie Institute, Paris, France and INSERM U333 – Pr Triebel, Gustave Roussy Institute, Villejuif, France.

1995-1996  Assistant Professor of Immunology, Department of Immunology, Laboratory of Tumor Immunology, CNRS URA 1484, Pr Bellet, University of René Descartes, Paris V, France.

Since 1996 Researcher at theCommissariat à l’Energie Atomique, Hemato-Immunology Research Department, Dr Carosella, Hospital Saint-Louis, IUH, CEA-DSV-DRM, Paris, France.

Scientific summary

The main results we obtained showed: (i) the role played by HLA-G expressed physiologically on extravillous cytotrophoblast in the maternal-fetal tolerance, (ii) the membrane expression of HLA-G isoforms with one, two or three extracellular domains and their inhibitory activity on the cytotoxic function of NK cells and CD8⁺ T cells, (iii) ectopic expression of HLA-G in solid tumors and its role in tumor escape from immune surveillance, and (iv) the neo-expression of HLA-G on a transplanted organ and its correlation with better graft acceptance. All this work demonstrates the role played by HLA-G as a molecule of immune tolerance. In addition, we described the production of soluble HLA-G by erythroid and endothelial progenitors very early in embryonic life. These results open new perspectives for application in the field of hematopoiesis and angiogenesis in which HLA-G may exert extra-immunological function.

Based on the tolerogenic properties of HLA-G, two clinical contexts are currently studied by our group centred in transplantation and oncology in which HLA-G will drive either benefit or deleterious actions. In the context of solid tumors, we have demonstrated: (i) the expression of HLA-G in tumors such as melanomas, breast and ovarian carcinomas in correlation with inflammation and tumor aggressiveness, (ii) the up-regulation of HLA-G expression by tumor environmental factors such as cytokines, and (iii) the biological relevance of HLA-G in permitting the evasion of malignant cells from anti-tumor immune response. HLA-G expression may constitute a target for anti-tumor therapy. In this regard, the development of an animal model allow us to validate in vivo the concept that the immunogenicity of HLA-G⁺ tumor cells may be enhanced by blocking function of HLA-G by using specific antibody thereby affecting the clinical course of HLA-G⁺ solid tumors. In the context of liquid tumors, the soluble form of HLA-G inhibits (i) the growth of malignant erythroid clones from patients with polycythemia vera, a myeloproliferative disorder characterized by erythroid lineage overproduction, and (ii) the proliferation of B cell lymphoma and myeloma cell lines (Brevet N° PCT/FR2009/000965). These observations reveal for the first time an unexpected role for HLA-G as a potential anti-tumor agent in myeloproliferative disorders, B lymphoma and myeloma. Altogether, these observations shed a new light on the role of HLA-G in oncology. Effects of HLA-G will depend on whether the tumor cells express or not inhibitory receptors for HLA-G. While constituting a way for solid tumors to evade immunosurveillance through inhibition of anti-tumor immune effectors, HLA-G may be able to inhibit tumor growth of liquid tumors expressing at least one of its receptors.

In the context of transplantation, we have conducted two approaches leading us to show: (i) a significant clinical correlation between a reduced incidence of acute and chronic rejection and HLA-G expression in patients following transplantation of heart, lung, liver, and kidney. The link between HLA-G and in vivo tolerance was provided by the demonstration that sHLA-G purified from plasma of HLA-G⁺ patients suppresses T cell alloproliferation in vitro. A positive correlation was clearly obtained between graft survival, HLA-G, and HLA-G-related immunological parameters such as IL-10, soluble CD4 or CD8, and CD3⁺CD4^low or CD3⁺ CD8^low suppressor T cells, which all may contribute to tolerance in HLA-G⁺ transplanted patients. (ii) In vivo induction of HLA-G was found in kidney-transplanted patients treated with a novel immunosuppressive therapy (i.e., CTLA4-Ig, Belatacept*) promoting high plasma levels of sHLA-G and better graft function and survival. Our data have important clinical implications: (i) measurement of HLA-G plasma levels may be used to monitor transplant patients expected to better accept their allograft, (ii) the amount of immunosuppressive drugs could thus be decreased in these HLA-G-positive patients, thereby reducing deleterious side effects, and (iii) treatment with HLA-G or derivatives may constitute a novel efficient anti-graft rejection therapy. In this regard, we demonstrated recently that adult bone marrow-derived mesenchymal stem cells (MSCs) secrete soluble HLA-G molecules which play a major role in the immunosuppressive properties of these cells. Thus, human MSCs expressing HLA-G constitute a novel therapeutic approach aimed at preventing rejection after solid and liquid tissue transplantation. Moreover, due to their multipotency, the use of these cells has generated increasing interest in regenerative medicine. In this regard, we are involved in a European project aimed at defining the use of allogeneic MSC in bone repair.