Adoptive cell transfer (ACT) immunotherapy is showing impressive responses in hematological cancers and in metastatic melanoma. However, both the magnitude of tumor responses and the fraction of patients benefitting from this novel therapeutic approach remains limited. T lymphocytes prepared for ACT are generally terminally differentiated, resulting in inefficient engraftment. It has been shown that the infusion of T cells with a self-renewing, memory phenotype confers a stronger and more sustained anti-tumor response. Recently, it is becoming clear that T cell fate is tightly linked with specific metabolic characteristics. Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how pyruvate oxidation and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive.
We genetically and pharmacologically interfered with MPC activity in mouse and human T cells. Mechanistically, we performed metabolomics and epigenetic analyses. We translated our findings in a xenograft model for anti-CD19 chimeric antigen receptor (CAR) T cell treatment for human acute lymphoblastic leukemia (ALL).
Genetic deletion of MPC drives CD8+ T cell differentiation towards a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production through glutamine and fatty acid oxidation, resulting in increased histone acetylation. The ensuing enhanced chromatin accessibility favored memory T cell differentiation, orchestrated by the transcription factor RUNX1. We used a small molecule MPC inhibitor to epigenetically imprint a memory phenotype during human CAR T cell manufacturing. Infusing unconditioned CAR T cells could not prevent mortality in mice with advanced ALL, while ACT with metabolically conditioned CAR T cells resulted in 100% complete responses. Similar results were obtained in a mouse melanoma model.
We show that metabolic intervention during CAR T cell manufacturing promotes memory T cell differentiation at the epigenetic level, allowing for a superior and long-lasting antitumor response in both hematological malignancies and solid tumors.
The authors.
Swiss Cancer League (KFS-4404-02-2018) and Roche pRED.
M. Wenes: Financial Interests, Personal and Institutional, Proprietary Information: University of Lausanne; Financial Interests, Institutional, Research Grant: Roche Glycart. D. Migliorini: Financial Interests, Institutional, Research Grant: Innosuisse. P. Ho: Non-Financial Interests, Personal, Advisory Board: Elixiron Immunotherapeutics; Financial Interests, Institutional, Funding: Elixiron Immunotherapeutics; Non-Financial Interests, Personal, Advisory Board: Acepodia; Non-Financial Interests, Personal, Advisory Board: Novartis. P. Romero: Financial Interests, Personal, Advisory Board: MaxiVax; Financial Interests, Institutional, Research Grant, University of Lausanne: Roche Glycart; Financial Interests, Personal and Institutional, Proprietary Information: University of Lausanne. All other authors have declared no conflicts of interest.