Among the available immunotherapies, CAR-T cell therapy has demonstrated remarkable efficacy against certain blood cancers, albeit only in about half of patients. A major contributing factor to this limitation lies in the premature dysfunction of these artificially engineered immune cells, cultivated in laboratory conditions.
This study*, published in Nature, was led by Alison Jaccard (Oncology department UNIL-CHUV) and directed by Dr. Mathias Wenes (UNIGE) and researchers of the Lausanne Branch of the Ludwig Institute for Cancer Research; Prof. Ping-Chih Ho, Group leader, and Prof. Romero, Deputy scientific managing director.
Protection against pathogens or cancer is mediated by strong adaptive immune responses initiated by the activation of clones of antigen-specific effector T cells. To sustain their rapid expansion to large numbers and effector functions, T cells activate an anabolic metabolism with high aerobic glycolysis, but also mitochondrial metabolism and oxidative phosphorylation. To ensure long-lived protective immunity against tumor recurrence, some of these effectors become long-lived memory T cells which requires metabolic shifts to oxidative phosphorylation and fatty acid oxidation. The researchers discovered how a specific metabolic pathway interacts with gene expression in T cells and limits their polyfunctionality, and how interfering with this pathway can improve cellular immunotherapy against cancer through memory T cell metabolic reprogramming.
Here, the team reports that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Serendipitously, they observed that IDH2 deletion promotes memory CD8+ T cell differentiation while preserving proliferation and effector functions. This surprising outcome seemed ideal to improve the ability of cell products to live longer and enhance anti-tumor immunity upon infusion to patients. Accordingly, they achieved this by simply introducing a step of IDH2 inhibition during ex vivo CAR T cell manufacturing. The modified manufacturing of engineered T cells does induce memory features and enhances antitumour activity in melanoma, leukemia and multiple myeloma. The were able to show in elegant genetic and biochemical experiments that IDH2 inhibition activates compensating metabolic pathways which causes a disequilibrium in metabolites regulating histone-modifying enzymes, which in turn maintains chromatin accessibility at key genes required for memory differentiation. They concluded that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but instead primarily instructs a metabolite constellation that epigenetically locks CD8+ T cells in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell therapeutic efficacy.
The research was generously supported by Oncosuisse, the Ludwig Institute for Cancer Research, the ISREC foundation and Roche. This work, under the umbrella of the Swiss Cancer Center Léman (SCCL), is a fruitful collaboration between the Lausanne University Hospital (CHUV), the University of Lausanne (UNIL), the Department of Oncology (CHUV), the Universities of Geneva (UNIGE), the University of lausanne (UNIL), the Geneva University Hospitals (HUG) and with Prof. Denis Migliorini (UNIGE/HUG) and Prof. Caroline Arber (UNIL-CHUV/LICR).
* Reductive carboxylation epigenetically instructs T cell differentiation