Dr Nathalie Rufer, Privat-Docent

Activité de recherche :

• Molecular and structural dissection of anti-viral and anti-tumor T-cell immune responses in humans

Mots clés :

• Tumor immunity, T-cell receptors, vaccination, T-cell differentiation, memory

Lien sur le site

Cytolytic CD8 T lymphocytes are responsible for specific-recognition and elimination of infected or transformed cells. Some but not all tumor antigen-specific T-cells can destroy diseased cells upon antigen specific recognition, in patients suffering from cancer. Therefore, a central aim is the identification of the type of T-cells and their T-cell receptors that are most efficient in anti-cancer therapy. For that purpose, we have recently developed a new molecular-based strategy that allows us for the first time to precisely assess human T-cell responses ex vivo by dissecting distinct T-cell subsets and anatomical compartments over time, before and during immunotherapy (Rufer, 2005). Complete in-depth studies in two patients showed that spontaneous priming led to the selection and expansion of dominant clonotypes of high TCR avidity to cognate tumor antigen and strong tumor reactivity. Remarkably, peptide vaccination successfully boosted the frequencies of these pre-existing clones within the circulating CD8 pool, indicating that spontaneously primed T-cell clones with high TCR avidity could be preferentially promoted through vaccination, and were also dominantly found at metastatic tumor sites in those patients (Speiser et al., 2006; Derré et al., 2007). Altogether, molecular characterization of tumor- and vaccine-induced antigen-specific T-cells can identify highly focused human immune responses.
The research work developed within my research group has been focused on three major aspects. First, we are pursuing the systematic characterization of T-cell mediated immunity in vaccinated melanoma patients by coupling the in vivo expansion, the acquisition of such attributes as memory, production of cytokines and lytic activity, and the selective processes that shape the repertoire of TCRs against tumor antigens. The second aspect is devoted on the comprehensive study of T-cell mediated immune responses to Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), and on the determination of similarities and differences with immune responses against tumor antigens. The third aim is to characterize the structural basis of TCR avidity for tumor antigens such as Melan-A/MART-1 and NY-ESO-1. Recently, we performed a extended and detailed structural and functional analysis of the TCR  repertoire towards the immunodominant epitope corresponding to the cancer testis antigen NY-ESO-1157-165 presented by HLA-A*0201. Collectively, the identification of dominant tumor specific T-cell clonotypes and their detailed characterization at the single cell level are key steps to better understand the relation between structural and functional features of TCRs. Expected results will provide key information to better understand the molecular basis of immune response dynamics, providing rationales and support for further the development of antigen-specific immunotherapy.

Références :

• Rufer N. (2005). Curr Opin Immunol. 17, 441-447.
  
• Speiser DE et al. (2006). J Immunol. 177, 1338-1348.
  
• Derré L et al., (2007). J Immunol. 179, 2368-2379.