Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

Abstract

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3a/b, is a central regulator of PD-1 transcription in CD8 þ T cells. Here, we show that the use of smallmolecule inhibitors of GSK-3a/b (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3a/b reduced PD-1 expression on CD8 þ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a þ (LAMP1) and granzyme B (GZMB) on CD8 þ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8 þ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8þ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706-17.Ó2017 AACR.

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

“…Our findings also showed that GSK-3 inhibition operated primarily via a reduction in PD-1 transcription on CD8 + T cells (Taylor et al, 2016(Taylor et al, , 2018. We further showed that SMIs against GSK-3 are as effective as anti-PD-1 Abs in restricting B16 and EL-4 tumor growth in mice (Taylor et al, 2018).…”

“…In this context, we have identified the enzyme glycogen synthase kinase-3 (GSK-3) as a major nexus in the control of PD-1 expression on T cells (Taylor et al, 2016). We also showed that small molecule inhibitors (SMIs) of GSK-3 can suppress tumor growth in a manner comparable to PD-1 Ab blockade (Taylor et al, 2018).…”

“…We originally demonstrated that the inhibition of serine/threonine kinase GSK-3 downregulates PD-1 expression, which enhances T cell responses against viral infections (Taylor et al, 2016(Taylor et al, , 2018. There are two ubiquitously expressed and highly conserved isoforms of GSK-3, GSK-3a and GSK-3b, which have shared and distinct substrates, as well as functional effects.…”

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

“…Both approaches aim to block the checkpoint signals that attenuate the function of activated Teffs, thus releasing Teffs from negative feedback control (19). PD-1/PD-L1 blockade has previously been shown to effectively reduce growth of EL4-OVA, MC38, and LLC tumors (20)(21)(22), while anti-CTLA-4 has not been as successful, at least as a monotherapy in tumors lacking expression of a strongly immunogenic antigen (23)(24)(25). PI3Kδ D910A mice were injected with either LLC-OVA or MC38-OVA tumors, and treated with 3 doses of antibody against CTLA-4 or PD-L1 ( Figure 4A).…”

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

“…Third, Li et al [76] showed that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and can induce phosphorylation-dependent proteasome degradation of PD-L1. A study by Taylor and colleagues [77] also reported that GSK3β inhibitors can downregulate PD-1 expression and enhance CD8+ T-cell function in cancer therapy. Thus, the combination of tideglusib, a GSK3β inhibitor, with anti-PD-1 therapy could be a promising strategy for melanoma treatment.…”