MEK Inhibition Acts on CD8⁺ T Cells to Enhance Antitumor Immunity

MEK1/2 inhibition can synergize with immunotherapies such as immune checkpoint blockade and adoptive T-cell transfer treatments due to MEK inhibition's influence on tumor immunogenicity and the tumor microenvironment. MEK inhibition can also lead to greater abundance of tumor-infiltrating CD8⁺ T cells, although the exact effects of MEK inhibition on these T cells have not been fully established. Verma and colleagues investigated this, finding that MEK inhibition enhanced tumor infiltration by effector CD8⁺ T cells, prevented CD8⁺ T-cell exhaustion, and promoted CD8⁺ T-cell activation, leading to reduced tumor growth and improved survival in cancer vaccine–treated mice. MEK inhibitor–treated CD8⁺ T cells exhibited metabolic alterations; specifically, their mitochondrial respiration was enhanced by increased fatty-acid oxidation. Metabolomic and lipidomic analyses of these T cells provided additional evidence that MEK inhibition increased fatty-acid metabolism, and further investigation revealed that MEK inhibition increased levels of the transcriptional coactivator PGC1α, which regulates energy metabolism–related genes, along with increasing fatty-acid oxidation–based cellular respiration by raising levels of the metabolic regulator SIRT3. In vitro and in vivo, MEK inhibitor treatment induced naïve CD8⁺ T cells to adopt a stem cell–like memory T-cell (T_SCM) phenotype, conferring them greater self-renewal capabilities, multipotency, and increased proliferative capacity. Mechanistically, MEK inhibition promoted the transition of naïve CD8⁺ T cells into T_SCM cells by delaying cell division, proliferation, and differentiation throughout T-cell receptor–mediated cell priming, maintaining CD8⁺ T cells at an early stage of differentiation without having an impact on effector function or activation. Notably, both hindering cell-cycle progression and enhancing metabolism were required for adoption of the T_SCM phenotype; neither alone was sufficient. Importantly, MEK inhibitor treatment of CD8⁺ T cells led to more potent antitumor efficacy with adoptive T-cell transfer therapy. In summary, this work reveals key insights into the role of MEK inhibition on functionally relevant aspects of antitumor immunity.

Verma V, Jafarzadeh N, Boi S, Kundu S, Jiang Z, Fan Y, et al. MEK inhibition reprograms CD8⁺ T lymphocytes into memory stem cells with potent antitumor effects. Nat Immunol 2020;22:53–66.

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