Non-Redundant Activity of GSK-3α and GSK-3β in T Cell-Mediated Tumour Rejection

Glycogen synthase kinase-3 (GSK-3α/β) has previously been identified as an upstream regulator of PD-1 gene expression in CD8+ T cells and GSK-3 inhibition is as effective as anti-PD-1 in the control of tumor growth. While GSK-3 has two co-expressed isoforms, GSK-3α and GSK-3β, their relative roles in regulating T cell activity are unclear. Here, using conditional gene targeting of each isoform, we demonstrate that both isoforms contribute to T cell function to different degrees. GSK-3β-/- mice were able to limit tumor growth to the same degree as GSK-3α/β-/- mice pointing to a dominate role for GSK-3α in tumor rejection. Interestingly, the loss of either GSK-3α or β increased expression of the transcription factor Tbet, but only the loss of GSK-3β reduced PD-1 expression, yet depletion of both isoforms led to maximum reduction of PD-1 expression. In terms of tumor infiltrating T cells (TILs), the loss of GSK-3α or β promoted an increase in interferon (IFN)-g expressing CD8+ TILs, while the individual loss of either isoform increased the presence of granzyme B (GZMB) expressing CD8+ TILs. These findings indicate that GSK-3 α or β isoforms have differential effects on PD-1, IFNg and GZMB expression, while operating in synergy to reduce PD-1 expression and promote the infiltration of tumors with CD4 and CD8 T cells. Overall, our data suggests a complex interplay of the isoforms in the control of tumour immunity.