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. 2022 Mar 28;10(3):e004026. doi: 10.1136/jitc-2021-004026

Figure 8.

Figure 8

eEF2K inhibition synergistically enhanced the therapeutic efficacy of PD-1 blockade in vivo. (A–E) C57BL/6 mice were implanted with B16F10 cells and co-treated with NH125 and PD-1 mAb. (A) A schematic view of the treatment protocol. (B) Photopraphs of B16F10 tumors harvested after euthanizing the mice. n=6 for each group. (C) The tumor growth of B16F10 cells in NH125 and/or anti-PD-1 antibody-treated C57BL/6 mice. (D) Plots for tumor weight. (E) CD8α and granzyme B in mouse tumor tissues of each group were determined by immunofluorescence. (F–I) C57BL/6 mice were implanted with Ctrl or sheEF2K-transfected B16F10 cells, and received PD-1, CD8α mAb treatment or IgG isotype control. (F) A schematic view of the treatment plan. (G) Photopraphs of mice tumors of each group at the end of the experiment. (H) Curves of tumor growth. (I) Plots for tumor weight. ∗∗P<0.01; ∗∗∗p<0.001. (J) A proposed model for eEF2K-induced GSK3β-phosphorylation-dependent PD-L1 stabilization and immunoregulation in melanoma. eEF2K overexpression in cancer cells phosphorylates GSK3β at serine 9 for GSK3β inactivation, leading to PD-L1 stabilization, enhanced PD-1 interaction and subsequent immunosuppressive microenvironment as a consequent. Therapeutic depletion or inhibition of eEF2K maintains GSK3β activity for phosphorylation-dependent proteasome degradation of PD-L1, thereby decreasing the cancer cells PD-L1 expression level and synergistically enhancing the therapeutic efficacy of PD-1 mAb therapy. eEF2K, eukaryotic elongation factor 2 kinase; GSK3β, glycogen synthase kinase 3 beta; mAb, monoclonal antibody; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1.