MEK1/2 inhibition enhances both the persistence and antitumor activity of CD8+ T cells in vivo.
Although adoptive T cell transfer therapy (ACT) has been a successful form of cancer immunotherapy, transferred T cells often become exhausted and lose their antitumor activity because of persistent stimulation in the tumor microenvironment (TME). Previous studies showed that inhibition of the kinases MEK1/2, components of the mitogen-activated protein kinase (MAPK) signaling cascade, with a small-molecule inhibitor (MEKi) potentiates the effectiveness of immunotherapies. In experiments with mouse tumor models, Verma et al. showed that MEKi increased the number of tumor-infiltrating CD8+ T cells and inhibited the exhaustion and enhanced the activity of these cells. MEKi-treated CD8+ T cells showed delayed cell cycle progression and enhanced mitochondrial biogenesis and function due to increased fatty acid–mediated metabolism. In tumor-bearing mice, MEKi induced the differentiation of CD8+ T cells into stem cell–like T (TSCM) cells in the TME. Compared to central memory and naïve T cell subsets, these TSCM cells showed enhanced self-renewability and greater expression of genes associated with an effector response. In vitro, MEKi-treated CD8+ T cells had enhanced recall responses to antigen stimulation and increased production of effector molecules. In a mouse model of ACT, MEKi-treated mice showed better antitumor responses and survival, which mostly depended on the presence of TSCM cells. In addition, MEKi-treated cells showed a more persistent memory phenotype compared to that of nonMEKi-treated cells. Together, these data suggest that CD8+ T cells can be reprogrammed by treatment with MEKi compounds to generate stem cell–like cells with enhanced persistence and antitumor activity, which may help to generate more effective forms of ACT.
