Small Molecule Inhibition of GSK-3 Specifically Inhibits the Transcription of Inhibitory Co-receptor LAG-3 for Enhanced Anti-tumor Immunity.

Christopher E Rudd, Kittiphat Chanthong, Alison Taylor

Cell reports 2020 Feb 18

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Immune checkpoint blockade using antibodies against negative co-receptors such as cytolytic T cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has seen much success treating cancer. However, most patients are still not cured, underscoring the need for improved treatments and the possible development of small molecule inhibitors (SMIs) for improved immunotherapy. We previously showed that glycogen synthase kinase (GSK)-3α/β is a central regulator of PD-1 expression, where GSK-3 inhibition down-regulates PD-1 and enhances CD8+ cytolytic T cell (CTL) function, reducing viral infections and tumor growth. Here, we demonstrate that GSK-3 also negatively regulates Lymphocyte Activation Gene-3 (LAG-3) expression on CD4+ and CD8+ T cells. GSK-3 SMIs are more effective than LAG-3 blockade alone in suppressing B16 melanoma growth, while their combination resulted in enhanced tumor clearance. This was linked to increased expression of the transcription factor, Tbet, which bound the LAG-3 promoter, inhibiting its transcription, and to increased granzyme B and interferon-γ1 expression. Overall, we describe a small molecule approach to inhibit LAG-3, resulting in enhanced anti-tumor immunity. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Christopher E Rudd, Kittiphat Chanthong, Alison Taylor. Small Molecule Inhibition of GSK-3 Specifically Inhibits the Transcription of Inhibitory Co-receptor LAG-3 for Enhanced Anti-tumor Immunity. Cell reports. 2020 Feb 18;30(7):2075-2082.e4