Figure 1.

Interference in PD-1 expression by small molecule GSK3 inhibitors. (a) Illustration of the PD-1/PD-L1 signaling axis, which suppresses cytotoxic T-cell tumor cell killing by inhibiting signal transduction by the T-cell antigen receptor (TCR) complex. PD-1 is expressed on “exhausted” T-cells, leading to the recruitment of the SHP2 phosphatase, which interferes in recruitment of signaling components to tyrosine-based motifs in post-TCR signaling complexes. This prevents the release of cytolytic granules. Constitutionally active GSK3 is responsible for preventing the transcriptional activation of the T-bet promoter (Tbx21). (b) Introduction of a GSK3 inhibitor (e.g., by a nanocarrier) allows restoration of T-bet expression, leading to transcriptional interference of the PD-1 promoter (Pdcd1) complex. The disappearance of PD-1 from the cell surface restores TCR signal transduction, allowing tumor cell killing by cytotoxic T-cells. In this sense, the transcriptional suppression of PD-1 exerts the same effect as blocking of the interaction of PD-1 with its ligand by antibodies.