Small Molecule Inhibition of Glycogen Synthase Kinase 3 (GSK-3) Specifically Inhibits the Transcription of Inhibitory Co-Receptor LAG-3 for Enhanced Anti-Tumor Immunity
21 Pages Posted: 2 Oct 2019 Sneak Peek Status: Review CompleteMore...
Immunotherapy has ushered in a new age with immune check-point blockade (ICB) for the treatment of various human cancers. Antibody blockade of the negative co-receptor programmed cell death-1 (PD-1) or its ligand, PD-L1 established this immunotherapeutic approach. However, the fact that most patients are not cured has led to a search for new checkpoint targets involving the development of small molecule inhibitors (SMIs). We have previously shown that the inactivation of the serine/threonine kinase glycogen synthase kinase (GSK)-3α/β down-regulates PD-1 expression for enhanced CD8+ CTL function and clearance of tumors and viral infections. In this paper, we now demonstrate GSK-3 SMIs and siRNA specifically inhibit transcription and downregulate LAG-3 on both CD4 and CD8+ T cells. This extends the targeting of GSK-3 to CD4+ T-cells, and in CD8+ T-cells, occurs independently of PD-1 down-regulation. Functionally, we found that GSK-3 SMI monotherapy was more effective than LAG-3 blockade but effectively synergises with anti-LAG-3 to limit B16 melanoma tumor growth. The enabling effect of GSK-3 SMIs on anti-LAG-3 therapy was linked to an increase in the presence of granzyme B (GZMB) and interferon-γ1 expressing CD8+ infiltrating T-cells in tumors. Overall, we describe for the first time a small molecule approach for the inhibition of transcription of inhibitory co-receptor LAG-3 for enhanced anti-tumor immunity
Keywords: Immune Checkpoint Blockade, PD-1, LAG-3, T-cells, GSK-3, Glycogen Synthase Kinase-3, immunotherapy, B16 melanoma
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