ED Sciences de la Vie et de la Santé
Roles of PCSK7 and PCSK9 in tumor progression and associated immune response
by Chloé PORCHERON (BoRdeaux Institute of onCology)
The defense will take place at 15h00 - Amphithéâtre BBS Université de Bordeaux, Bâtiment Bordeaux Biologie Santé (BBS), 2 rue Dr Hoffmann Martinot, 33000 Bordeaux
in front of the jury composed of
- Abdel-Majid KHATIB - Directeur de recherche - Université de Bordeaux - Directeur de these
- Nabil.G SEIDAH - Directeur de recherche - Université de Montréal - Directeur de these
- Ghislaine FONTES - Associée de Recherche - Université de McGill - Examinateur
- Claire DUBOIS - Professeure - Université de Sherbrooke - Examinateur
- Martin TEICHMANN - Professeur - Université de Bordeaux - Examinateur
- Bruno SEGUI - Professeur - Université de Toulouse - Rapporteur
- Fabrice LALLOUE - Professeur - Université de Limoges - Rapporteur
- Claude PERREAULT - Professeur - Université de Montréal - Examinateur
Proprotein convertases (PCs) are a family of 9 secretory serine proteases recognized for the cleavage of various substrates for their maturation. PCs are involved in many physiological processes due to substrate variability. Indeed, dysregulation of their expression or activity can lead to various pathologies including cancer. Although PCSK7 is the most ancient convertase in the PC family, its physiological roles remain poorly characterized. It is only recently that PCSK7 has been associated with lipid metabolism through regulation of apoB and apoA-V levels, without requiring any proteolytic activity. Which classifies PCSK7, like the last member PCSK9, as a PC endowed with non-enzymatic functions. PCSK7 is ubiquitously expressed in the body, however it is found enriched in lymphoid organs at the tissue level and in immune cells, and more particularly in T lymphocytes, at the cellular level. Despite these observations, the role of PCSK7 in the immune response remains largely unknown. To define a possible role of PCSK7 in immunity, we first focused on human databases to study the expression of PCSK7 among all factors responsible for the immune response. These data highlighted a positive correlation between PCSK7 mRNA expression and those of some immune checkpoint proteins, which are surface proteins inhibitors of T cell function. We thus studied intracellular and cell surface levels of immune checkpoint proteins by modulating the expression of PCSK7 in different in vitro models including a human hepatocyte cell line, murine T lymphocytes isolated from the spleen and human T lymphocytes from blood samples. Thus, these studies have demonstrated the important role of PCSK7 in regulating the level of diverse immune checkpoint proteins. Immunotherapies based on immune checkpoint inhibitors have represented a real advance in cancer treatment, but they remain ineffective for most patients. Indeed, we studied the possible therapeutic role of PCSK7 inhibition in tumor progression, alone or in combination with PCSK9 inhibition which is already recognized as an important mediator of the antitumoral immune response. Thus, the single deletion of Pcsk7 or Pcsk9 in mice allows a reduction in the number of liver metastases of colorectal cancer by about 50%, while the double deletion Pcsk7/Pcsk9 induces a reduction in metastatic development by about 90%. In addition, the deletion of Pcsk7 and Pcsk9 promotes the infiltration of CD8+ T lymphocytes into liver tumors and reduces the expression of immune checkpoint proteins, thus improving the cytotoxic activity of infiltrated T lymphocytes. To conclude, this study describes a new role of PCSK7 in immunity, through the regulation of immune checkpoint protein expression levels, thus rationalizing the use of PCSK7 inhibitors in immunotherapies alone or in combination with a PCSK9 inhibitor in cancer treatment.