Huntington et al. found that inhibition of glycogen synthase kinases 3 (GSK-3) by elraglusib triggered pyroptosis and sensitized CRC tumor cells to T- and NK-mediated cytotoxicity while also enhancing immune cell effector function. Elraglusib synergized with anti-PD-L1 in a microsatellite-stable CRC model, increasing cytotoxic immune cell infiltration and extending survival. Plasma samples from patients treated with elraglusib revealed cytokine markers of response to therapy. Paired tumor biopsies demonstrated lower expression of inhibitory checkpoints and higher expression of T cell activation markers in TILs post-elraglusib treatment.
Contributed by Ute Burkhardt
ABSTRACT: Inhibition of GSK-3 using small-molecule elraglusib has shown promising preclinical antitumor activity. Using in vitro systems, we found that elraglusib promotes immune cell-mediated tumor cell killing, enhances tumor cell pyroptosis, decreases tumor cell NF-_B-regulated survival protein expression, and increases immune cell effector molecule secretion. Using in vivo systems, we observed synergy between elraglusib and anti-PD-L1 in an immunocompetent murine model of colorectal cancer. Murine responders had more tumor-infiltrating T-cells, fewer tumor-infiltrating Tregs, lower tumorigenic circulating cytokine concentrations, and higher immunostimulatory circulating cytokine concentrations. To determine the clinical significance, we utilized human plasma samples from patients treated with elraglusib and correlated cytokine profiles with survival. Using paired tumor biopsies, we found that CD45+ tumor-infiltrating immune cells had lower expression of inhibitory immune checkpoints and higher expression of T-cell activation markers in post-elraglusib patient biopsies. These results introduce several immunomodulatory mechanisms of GSK-3 inhibition using elraglusib, providing a rationale for the clinical evaluation of elraglusib in combination with immunotherapy. STATEMENT OF SIGNIFICANCE: Pharmacologic inhibition of GSK-3 using elraglusib sensitizes tumor cells, activates immune cells for increased anti-tumor immunity, and synergizes with anti-PD-L1 immune checkpoint blockade. These results introduce novel biomarkers for correlations with response to therapy which could provide significant clinical utility and suggest that elraglusib, and other GSK-3 inhibitors, should be evaluated in combination with immune checkpoint blockade.