Nat Immunol: Inhibiting MEK reprograms CD8-T cells as tumor-resistant memory stem cells

In recent years, with the increasing and in-depth basic research on tumors, the treatment methods of cancer applied to the clinic are emerging.
targeted therapy and immunotherapy are based on basic research to obtain treatments dedicated to precision medicine.
but immunotherapy has received many limitations in clinical application, one of which is that the lack of effect T cells leads to weak persistence and the treatment can not achieve the desired results.
, there is an urgent need to develop reagents that can overcome these limitations.
years, the mechanical link between T-cell metabolism and its effect function and the development of failure has become an important therapeutic target for cancer patients.
in tumor microenceptic environment (TME), the continuous stimulation of silk division stimulates the excessive division of the effect cells, producing a esophology of failure, which manifests it as the weakening of the function of the effect cells and impairs the production of immune memory.
previous studies have shown that MEK inhibitors (MEKis) enhance the anti-tumor effects of step-by-step T-cell metastasis therapy (ACT).
meki works in part by increasing tumor immunogenicity and regulating TME.
, meKi's effects on T-cell function, its differentiation and memory, are poorly informed.
, 23 November 2020, Samir N. Writing online in the journal Nature Immunology, the Khleif team studied the role of MEK inhibitors in the reprogramming of CD8-T cell metabolism and cell cycle progression, as well as their immunomodulation of TME, revealing that MEK inhibitors can reprogram CD8-T lymphocytes into memory stem cells with powerful anti-tumor effects.
researchers first tested the immune effects of MEK1/2 inhibitors in mouse tumor models carrying specific antigens TC-1 (HPV16E7) and B16F10 (gp100).
, they evaluated MEKi's expression of p-MEK1/2 and p-ERK1/2 in TME effect cells.
results showed that although MEKi therapy in vaccinated animals significantly reduced the frequency of P-MEK1/2 plus and p-ERK1/2 plus CD8 plus T cells in TME, there was a significant increase in total and antigen-specific CD8 plus T cells.
a large number of antigen-specific CD8-T cells to express granulase B, indicating that MEKi leads to the amplification of TME functional antigen-specific effect cells.
these data show that MEK inhibition enhances tumor immersion in effect CD8-T cells, prevents failure, and keeps effect CD8-T cells active.
, the researchers explored the effects of MEK1/2 inhibition on T-cell metabolism based on metabolomics.
first, the mitochondrial mass of CD8-T cells in TME was observed, and the mitochondrial mass of meki-treated inoculated animals increased significantly compared to control animals.
, MEKi treated cells with dense mitochondrials and tightly stacked crucibles, indicating a complete redox mechanism and enhanced breathing capacity.
these data demonstrate increased metabolic adaptability and greater reliance on mitochondrial breathing by MEKi-treated CD8-T cells.
then, they tested the relative contribution of glucose and fatty acids (FAs) as MITR mitochondrial respiration substrates treated by MEKi, and found that glucose was not prioritized as an energy-producing substrate in MEKi-treated CD8-T cells.
the increase in the expression of CPT1a (THE speed limit enzyme of FAO 20), the intake of BODIPY (a pro-lipid probe, as an indicator of lipid intake) increased, thus showing an increase in FAs intake of CD8 plus T cells treated by MEKi.
addition, the significant increase in PCC1 alpha, a protein involved in mitochondrial biosynthetics, confirmed that MEK inhibition enhanced the metabolism of CD8-T cells.
well known, MEK1/2, ERK1/2, and cell cycle protein D1 are involved in linking external silk-promoting signals to in-cell metabolic proteins, including PCC1 alpha and SIRT3.
researchers found that MEK inhibition reduced the expression of p-ERK1/2 and cell cycle protein D1, correspondingly increasing the expression of PPC1 alpha.
After metabolic and lipid histological analysis of CD8 plus T cells treated by meki, they also observed that, unlike primitive cells, cells in the MEKi treatment group showed high proliferation capacity, higher expression of Sca1, and lower mitochondrial potential, in addition to higher memory and active markers.
And in MEKi-treated CD8-plus T cells, the expression of Kruple sample factor 2 (KLF2) associated with increased self-renewal, prolonged survival, and reduced apoptosis was increased, which also showed reduced apoptosis, indicating the generation of TSCM.
these TSCM cells, unlike central memory (TCM) cells, have higher self-renewal, plocytic and proliferation capabilities, and higher effect gene methylation.
, the researchers tested the effects of MEK1/2 inhibition on TSCM cell production in human CD8 plus T cells.
results show that, unlike Tnaive cells, TSCM cells have lower effect gene methylation and Tcf7 open bits.
these MEKi-induced TSCM cells show strong cellular activity, high antigen-specific recall responses, and extended lifetime.
MEKi induced stem cell memory of human CD8-T cells, the study demonstrated that MEK1/2i induced strong anti-tumor activity by reprogramming the metabolism of effect CD8-T cells by inhibiting the MAPK pathway.
During the initial antigen initiation, MEK1/2i inhibits the cell cycle protein D1, which promotes the production of stem cell-like memory (TSCM) cells by regulating the ERK 1/2-cell cycle protein D1-PGC 1 alpha-SIRT 3-FAO pathway.
these TSCM cells have lower effect gene methylation and Tcf7 open bits than Tnaive cells with higher self-renewal, plocyte and proliferation capabilities, and higher effect gene methylation.
, MEKi causes CD8-T cells to be reprogrammed to form TSCM, which serves as a repository of effect T-cells with effective therapeutic characteristics.
。