Non-redundant activity of GSK-3α and GSK-3β in T cell-mediated tumor rejection

Glycogen synthase kinase-3 (GSK-3) is a positive regulator of PD-1 expression in CD8+ T cells and GSK-3 inhibition enhances T cell function and is effective in the control of tumor growth. GSK-3 has two co-expressed isoforms, GSK-3 alpha and GSK-3 beta. Using conditional gene targeting, we demonstrate that both isoforms contribute to T cell function to different degrees. Gsk3b(-/-) mice suppressed tumor growth to the same degree as Gsk3a/b(-/-) mice, whereas Gsk3a(-/-) mice behaved similarly to wild-type, revealing an important role for GSK-3 beta in regulating T cell-mediated anti-tumor immunity. The individual GSK-3 alpha and beta isoforms have differential effects on PD-1, IFN gamma, and granzyme B expression and operate in synergy to control PD-1 expression and the infiltration of tumors with CD4 and CD8 T cells. Our data reveal a complex interplay of the GSK-3 isoforms in the control of tumor immunity and highlight non-redundant activity of GSK-3 isoforms in T cells, with implications for immunotherapy.

Automated summary

GSK-3 plays a crucial role in T cell function and tumor immunity, with the isoforms GSK-3α and GSK-3β having differential effects on immune responses and tumor infiltration, working together to control PD-1 expression and tumor growth.