Thursday Seminar-invited speaker: Ludovic Martinet (Toulouse)

T cell Immunotherapy: thinking beyond inhibitory receptors. Although immune checkpoint blockade (ICB) such as anti-PD-1 has represented a turning point in cancer care, clinical responses are not observed in the majority of cancer patients. The mechanisms underlying this lack of responsiveness are still poorly understood and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most studies focus on inhibitory receptors, signals transmitted through activating receptors also critically impact CD8+ T cell cancer immune surveillance and ICB efficacy. Indeed, we recently discovered that the loss of the activating receptor CD226 restrains CD8+ T cell functions and the therapeutic efficacy of cancer immunotherapy (Weulersse et al, Immunity. 2020, Braun et al, Immunity. 2020). More recently, we focused on CD137 (4-1BB) activating receptor, an enigmatic yet, promising target for immunotherapy. Through epigenetic, single cell transcriptomic and functional assays, using CD137 conditional knockout mouse models and agonist antibodies, our study revealed the implication of CD137 (4-1BB) signaling in T cell exhaustion program (Pichler et al, immunity. 2023). Understanding the cellular process that drive T cell dysfunction has crucial implications for the treatment of cancer and infectious diseases. Thus, our study, that uncovers the importance of CD226 and CD137 pathways in T cell dysfunction, could have broad applications for immunotherapy.