Mécanismes cellulaires et moléculaires de l'épuisement clonal

 

Hélène Decaluwe

Centre de recherche du CHU Sainte-Justine

 

Domaine : maladies infectieuses et immunitaires

Programme chercheurs-boursiers-cliniciens - Junior 1

Concours 2017-2018

Potent adaptive immune responses are essential to eliminate infected or transformed cells. The incapacity to generate effective cytotoxic responses allows for persistence of the virus and tumor evasion and progression. In the context of chronic antigenic stimulation, this failure of the immune system is driven by inhibitory receptors expressed at the surface of T cells.  These inhibitory receptors directly restrain the effector functions of the cells. Several environmental factors including cytokines were demonstrated to drive this state of exhaustion.  We have recently shown that IL-2 and IL-15 directly control key aspects of T cell exhaustion of CD8 T cells.

We now want to tackle the cytokine-dependent signaling pathways and transcriptional network that dictate T cell programming towards exhaustion. We further want to determine the epigenetic modifications induced by IL-2 and IL-15 during chronic antigenic stimulation. These results will uncover fundamental mechanisms dictating lineage choices during chronic viral infections. It will demonstrate that properly targeting cytokine-pathways may significantly improve the managements of patients with chronic infections or cancers.

Immune checkpoint blockade with antibodies against inhibitory receptors expressed on T cells  has been shown to restore potent functions in exhausted T cells and allow for viral elimination or tumor control. This approach is currently tested in clinical trials with unprecedented results. Because cell-based therapies generated ex vivo may become exhausted, we want to evaluate the benefice of combining immune checkpoint blockade with novel NK-cell based immunotherapies to treat pediatric neuroblastoma, the most frequent extracranial tumor of childhood who has poor survival rates.

We further want to demonstrate that severe combined immunodeficiency patients treated for their lethal immunodeficiency by hematopoietic stem cell transplantation may also greatly benefit from immune checkpoint blockade particularly if chronically infected. Collectively, this work will modify the way we treat patients with immune-related disorders, including cancers and chronic infections.