Adoptive T-cell therapy has demonstrated remarkable activity in refractory malignancies; however, the short survival of these cells in some patients results in treatment failure. CD8+ T-cells with self-renewable stem cell memory (TSCM) phenotype persist longer than the effector cells. Hence pharmacologic agents that maintain lymphocytes in TSCM phenotype may benefit the adoptive T cell-transfer strategies as well as combination immunotherapies. Small-molecule inhibitors of mitogen-activated protein kinase (MEKi) have been used for treatment of solid tumors. Here we report that inhibition of MEK enhances immune-driven antitumor response. We show that MEKi prevents the terminal differentiation and exhaustion of CD8+ T-cells in the tumor microenvironment. Interestingly, we further observed that MEKi leads to a significant increase in the CD62LhiCD44loSca1+ cells with low mitochondrial potential that are defined as TSCM CD8+ cells. Furthermore, ex vivo MEKi-treated CD8+ cells demonstrated a significantly higher antitumor activity in tumor-bearing mice. These MEKi treated CD8+ T-cells have higher mitochondrial respiration, which is fueled by fatty acid oxidation and exhibit significantly enhanced spare respiratory capacity (SRC). In addition, MEKi-treated cells have higher metabolic fitness, making them resistant to terminal exhaustion upon cell activation. Since OX40 co-stimulatory signals potentiate the self-renewal and homeostatic capacity of memory T-cells, we treated the tumor-bearing mice with MEKi in combination with OX40 agonistic antibody. Combining MEKi with OX40 agonist antibody significantly enhanced anti-OX40 antitumor effect. These data highlight the ability of pharmacologic MEK inhibition in inducing TSCM, which can be used ex vivo to enhance the potency of T-cell therapies and in vivo in combination immune therapy.

Citation Format: Vivek Verma, Shamim Ahmad, Peng Zeng, Mikayel Mkrtichyan, Simon T. Barry, Paul D. Smith, Paulo C. Rodriguez, John E. Janik, Seema Gupta, Samir N. Khleif. MAP kinase inhibition induces metabolic reprogramming in T-cells leading to induction of stem cell memory CD8 cells that enhance potency of adoptive cell therapy and anti-OX40 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4717.