The role of HSD11B1 in immune cell subpopulations in a human model

Diplôme Master The role of HSD11B1 in immune cell subpopulations in a human model eng 2020-11-20 author Paulhan Sara Rita 853822 director Bourquin Carole 0000-0003-3862-4583 854541 Immune cells have a critical role in the restriction of the cancer development. Usually, the T cells get rid of infections, but when some host cells abnormally proliferate, the T cells are recruited to kill those cancerous cells. However, the tumor cells can inhibit the immune response by activation blockades, as known as immune checkpoints. At the beginning of the 21st century, immunotherapy against the cancer, based on the inhibition of those brakes, such as antibody anti-PD-1 (programmed cell death 1), has been developed. Even so, this therapy work for less than 50% of the patients. That is why new targets must be found to improve the immunotherapy. Otherwise, endogenous glucocorticoids are known to decrease the immune cells’ activation. The 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) is an enzyme that convert the inactive form of glucocorticoids in the active form, which binds to the glucocorticoid receptor in the cell nucleus and induce a decrease of the immune response by a modulation of the genes transcription. A cohort study of the TCGA has shown a correlation between the prognosis of the renal cell cancer and the expression rate of HSD11B1. Consequently, assays have been done in the mouse model, and HSD11B1 has shown to have an impact in vitro, on the dendritic cells and on T cells, respectively. In this study, first I want to see an effect of HSD11B1 in vitro, on human cell activations. Then, the aim is to know in which immune subpopulation it plays its main role. The hypothesis is that HSD11B1 is implicated in the mechanism of antigen presentation by the dendritic cells and in the T cells activation. The purpose of this project is to know the role of that enzyme on the immune cells and particularly in their activation. The aim is to apply the results to use HSD11B1 as a new target to improve the immunotherapy efficacy. The project was divided in two parts: antigen recall assays on human PBMC with CMV peptides to understand the role of HSD11B1 on T cells’ activation and then RNA extraction followed by qPCR to determine the expression rate of HSD11B1 in immune cell subpopulations. Based on the results, it seems that HSD11B1 has an impact on the T cells’ activation, through the conversion of cortisone in cortisol. It seems also that it is more expressed in the dendritic cells than in CD4+ and CD8+ T cells and that the cells’ activation has a moderate impact on its expression. Those results must be confirmed by the reproduction of the experiments, but the use of HSD11B1 as a target for improving the anti-PD1 therapy in humans is a perspective. Dewey 615 Master en Pharmacie 31 Section des sciences pharmaceutiques 17 false 1278 Immunopharmacologie du cancer 793d5b7d-e7e9-4bd5-acc9-b37bfe7f14bd Master thesis Restricted 201128012205_paulhan0__TPR.pdf 1173286 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Paulhan, Sara Rita