MEK inhibition caused naïve CD8+ T cells to adopt a stem cell–like memory T-cell (TSCM) phenotype.
Major Finding: MEK inhibition caused naïve CD8+ T cells to adopt a stem cell–like memory T-cell (TSCM) phenotype.
Concept: TSCM cells had higher self-renewal, multipotency, and enhanced proliferation, aiding efficacy.
Impact: This provides a mechanism for T-cell differentiation and a strategy to enhance ACT and other immunotherapies.
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 (TSCM) phenotype, conferring them greater self-renewal capabilities, multipotency, and increased proliferative capacity. Mechanistically, MEK inhibition promoted the transition of naïve CD8+ T cells into TSCM 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 TSCM 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.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.