Exhausted T cells were first discovered in LCMV virus infections where chronic stimulation due to remaining virus antigens leads to T cells that stop responding to stimulation and lose their functionality (cytokine secretion and cytotoxic activity). The same phenotype was afterwards found in the tumor microenvironment where a lot of T cells were found to be “anergic”.
Reversing their loss of functionality as a therapeutic strategy has made the characterization of these exhausted T cells a priority. Their phenotype is currently defined by an increase in the expression of a specific set of cell surface markers such as PD-1, TIM-3 and LAG-3. As exhaustion builds, the expression of these marker increases while T cell functionality decreases. The loss of functionality is defined by a reduction in cytokine secretion, proliferation and cytotoxic activity in the presence of an antigen. To evaluate this phenotype in more depth, transcription factors can also be monitored. For example, BLIMP-1 and BATF, which play a role in PD-1 expression, are shown to increase following exhaustion.
Using primary immune cells, in vitro bioassays were developed to better screen the potential effect of new therapeutics on exhausted T cells. Their ability to reverse the exhausted phenotype and facilitate the anti-tumour immune response can, as a result ,be assessed early-on in the drug development process.
- Optimization of T cell exhaustion method
- Confirmation of exhaustion
- Testing of therapeutic candidates (examples of anti-PD1 and anti-CD137)
Senior Scientist Immuno-Oncology
Juliette holds a Master degree in Biochemistry and Cellular and Molecular Biology from the Université Catholique de Louvain (UCL), which included an internship at UCB. After complementing a 4 year doctoral research project on the inhibition of immune responses in cancer at the Ludwig Institute for Cancer Research in Brussels, she joined ImmunXperts as Senior Scientist in immuno-oncology.
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