Mechanisms of regulation of HLA-G molecule expression
The group investigates the mechanisms of regulation of HLA-G immune checkpoint expression in normal and pathological situations, mainly in oncology (tumor escape) and transplantation (graft maintenance). The objective is to provide tools to modulate its expression according to the pathological context and to identify prognostic markers of the evolution of patients.
The team initially established that HLA-G expression is controlled at the transcriptional level by an atypical promoter compared to classical HLA class I genes, but also at the post-transcriptional level including alternative splicing, messenger stability, translation and transport of the protein to the cell surface. Four aspects are explored from a fundamental point of view: (i) the influence of epigenetic mechanisms (ii) the identification of the transcriptional machinery (iii) the effect of microenvironmental factors and (iv) the impact of gene polymorphism. The mechanisms leading to inter- and intra-tumor heterogeneity of HLA-G and PD-L1 immune checkpoint expression in clear cell renal cell carcinoma are also studied.
The team has been coordinator of several collaborative Franco-Brazilian projects (CAPES-COFECUB, Ciênca sem fronteiras, Sorbonne Paris Cité and ANRS programs). The partner laboratory, located at the Faculty of Medicine of Ribeirão Preto, is attached to the University of São Paulo.
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Main contributions :
- Identification of microenvironmental factors and target sites involved in the regulation of HLA-G expression (IL-10, TNF-alpha, interferons, glucocorticoids, hypoxia, AIRE).
- Characterization of the mechanisms of HLA-G repression: DNA methylation, histone modifications and RREB1 factor.
- Demonstration of the impact of polymorphisms of the 5 'and 3' untranslated regions on the HLA-G gene expression in vitro and in vivo.
- Identification of new HLA-G alleles and alleles associated with pre-eclampsia, malaria and HCV/HIV infection.
- Multicentric study on the expression of HLA-G in glioblastoma and its impact on patient survival.