Mnemo Therapeutics, a biotechnology company developing transformational immunotherapies, today announced a publication in Nature Communications demonstrating that the histone lysine methyltransferase enzyme Suv39h1 plays not only a key role in T cell persistence, but also in T cell activation and exhaustion. This research was conducted at Institut Curie between the lab of Sebastian Amigorena, Ph.D., CNRS research director, head of the Immune Responses and Cancer Team (Immunity and Cancer Unit – Institut Curie/Inserm) and scientific co-founder of Mnemo, and the lab of Eliane Piaggio, Ph.D., Inserm research director and head of the Translational Immunotherapy Team (Immunity and Cancer Unit, Institut Curie/Inserm).
“T cell exhaustion and lack of persistence are two key challenges that hinder effective and durable immunotherapy treatments for tumors,” said Mnemo Chief Executive Officer, Robert LaCaze. “Through Suv39h1 inactivation, Mnemo aims to create therapies with increased durability and activity.”
Previous research, exclusively licensed to Mnemo from the lab of Dr. Amigorena, demonstrated that Suv39h1 is a key enzyme involved in the epigenetic regulation of immune cell memory, and that deletion of Suv39h1 results in increased immune cell memory and more durable therapeutic responses. The research demonstrated in the Nature publication goes on to show that this enzyme is a key factor in regulating T cell exhaustion.
“As is known, the potency of current treatments such as immune checkpoint inhibitors (i.e. anti-PD-1) is limited by repeated stimulation of T cells in a tumor rich environment, resulting in T cell exhaustion,” said Dr. Amigorena. “The current study showcases that Suv39h1 acts as an epigenetic checkpoint inhibitor that, when coupled with anti-PD-1 treatment, results in increased T cell activity and decreased T cell exhaustion.”
Key takeaways from the study include:
- Suv39h1 KO CD8+ T cells are more responsive to T-cell receptor (TCR) activation and become highly cytolytic following PD-1 blockade, resulting in increased tumor killing potency.
- Deletion of Suv39h1 resulted in higher CD8+ T cell tumor infiltration when coupled with anti-PD-1 treatment.
- CD8+ T cells in Suv39h1 KO mice treated with anti-PD-1 displayed the highest level of a protease (GZMb) responsible for T cell induced apoptosis of tumor cells, despite displaying elevated levels of biomarkers associated with exhaustion.
- Suv39h1 deletion resulted in increased chromatin accessibility in regions responsible for immune cell signaling and cytotoxicity during anti-PD-1 treatment, compared to WT with anti-PD-1 treatment.
- Inhibition of Suv39h1 via small molecules mimicked Suv39h1 deletion in mouse models, reinforcing that this enzyme is playing a direct role in T cell activity.
“Limited potency, durability, and cancer-specific targets impede the efficacy of current immunotherapies, leading to off-target side effects and patient relapse,” said Mnemo Co-Founder and Chief Operating Officer, Alain Maiore. “Alongside our EnfiniT Discovery Engine that identifies novel cancer targets, this research demonstrates Mnemo’s commitment to addressing multiple bottlenecks in the efficacy of immunotherapy, as well as bringing solutions to patients.”