Glycogen synthase kinase (GSK-3) inactivation synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy
Janna Kruger1,2, Alison Taylor3,4 and Christopher Rudd1,2,4 1Division of Immunology-Cell Therapy, Research Center Maisonneuve-Rosemont Hospital (CR-HMR) Montreal, Quebec H1T 2M4; 2Department of Microbiology, Infection and Immunology, Universite de Montreal, Montreal, Quebec; 3Leeds Institute of Cancer & Pathology, St James's University Hospital, Beckett Street, Leeds LS9 7TF; 4Department of Pathology, Cambridge University, Cambridge, United Kingdom
Immune checkpoint blockade (ICB) of negative co-receptors on T-cells such as cytotoxic T-cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) is a promising approach for the treatment of cancer. Despite this success, the poor prognosis for most patients continues to highlight a need for developing novel clinical interventions. In this context, we identified the enzyme glycogen synthase kinase-3 (GSK-3) as the major regulator of PD-1 expression on T-cells (Taylor et al., 2016 Immunity). We have shown that small molecule inhibitors (SMIs) of GSK-3 are as effective as anti-PD-1 in controlling the growth of lymphomas (Taylor et al., 2017 Can Res; Krueger and Rudd, Immunity 2017). Further, GSK-3 inactivation regulates the transcription factor T-bet which up-regulates interferon gamma (IFNγ) and granzyme B (GZMB) . Here, we show that GSK-3 SMIs can synergize with anti-PD-1, anti-CTLA-4 or radiation to eliminate solid tumors that are otherwise resistant to anti-PD-1, or anti-CTLA-4 inhibition alone. GSK-3 inactivation is therefore an immune-sensitizer for ICB therapy. On a cellular level, GSK-3 inactivation preferentially down-regulated PD-1 on CD8+ tumor infiltrating T-cells compared to CD4 and NK cells as documented in response to GSK-3 SMIs and in gsk3-/- conditional mice. At a molecular level, GSK-3 SMIs inhibited PD-1 transcription, increased granzyme B (GZMB)/ interferon-gamma1 (IFNγ) transcription and directly acted upon glycogen synthase to skew metabolism towards greater glycolysis. GSK-3 regulation of PD-1 expression was mediated primarily via CD28 co-stimulation. Our next generation approach using small molecule inhibitors to down-modulate PD-1 expression and synergy with immune check-point blockade represents a potential breakthrough in the development of new combination therapies for the treatment of cancer patients.
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