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-3α/β, is a central regulator of PD-1 transcription in CD8⁺ T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/β (GSK-3i) to reduce <i>pcdc1</i> (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-3α/β reduced PD-1 expression on CD8⁺ 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 <i>Tbx21</i> (T-bet) transcription, and the expression of CD107a⁺ (LAMP1) and granzyme B (GZMB) on CD8⁺ T cells. Finally, the adoptive transfer of T cells treated <i>ex vivo</i> 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⁺ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.<b>Significance:</b> These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8⁺ 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. <i>Cancer Res; 78(3); 706-17. ©2017 AACR</i>.