MEK inhibition reprograms CD8+ T lymphocytes into memory stem cells with potent antitumor effects

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

“…The mechanism by which MEKi affects the T cell mediated immunity is relatively unknown due to contradictory preclinical data. While some murine studies demonstrated that neoadjuvant MEK inhibition generate memory T cells with increased effector functions, others have shown that MEKi impairs T cell proliferation and function [110]. Given the lack of concrete evidence, further investigation is needed to determine whether MEKi offers additional clinical benefits when used in combination with TIL-ACT or BRAFi + TIL-ACT.…”

State-of-Art of Cellular Therapy for Acute Leukemia

“…As such, investigators have utilized small molecule inhibitors during cell manufacturing to finetune the signaling pathways to improve immune cell persistence. Among many inhibitors, the recent application of the mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, phosphatidylinositol 3-kinase (PI3K)-δ inhibitor, Idelalisib, or the bromodomain and extra-terminal motif (BET) protein inhibitor, JQ1, to the ex vivo expansion of T cells, has shown to significantly enhance the persistence and therapeutic efficacy of ACT in various preclinical cancer models [ 131 , 132 , 133 ]. Expansion of T cells in the presence of these inhibitors commonly skewed them towards stem cell-like memory T cells that are associated with better self-renewability and proliferative capacity.…”

“…Expansion of T cells in the presence of these inhibitors commonly skewed them towards stem cell-like memory T cells that are associated with better self-renewability and proliferative capacity. Mechanistically, MEK1/2 inhibitor delays cell division and enhances mitochondrial fitness with increased fatty acid oxidation for energy generation [ 131 ]. Idelalisib attenuates activation signal of T cells from the engagement of TCR, co-stimulatory receptors, and cytokine receptors [ 132 , 134 ], and JQ1 suppresses the expression of transcription factor BATF in CD8 + T cells, a transcription factor involved in differentiation of CD8 + T cells into effector T cells [ 133 ].…”

Divergent clonal differentiation trajectories establish CD8+ memory T cell heterogeneity during acute viral infections in humans

“…Given the phenotypic and functional similarities of T SCM to naive T cells, it is possible that a subset of T SCM may represent clones that fail to fully undergo differentiation in acute responses. Inhibition of the mitogen-activated protein kinase pathway, a key signaling pathway for T cell activation, was recently shown to favor T SCM differentiation, suggesting that limited acute activation may lead to clonal skewing toward a T SCM fate (Verma et al, 2021). Conversely, mouse studies have shown that repeated vaccinations lead to substantial memory T cell expansions consisting primarily of T EM , rather than T CM (Masopust et al, 2006;Vezys et al, 2009).…”