Abstract A59: Inhibition of Glycogen Synthase Kinase 3 (GSK-3) synergizes with anti-PD-1 by potentiating tumor-infiltrated CD8+ T-cells

Abstract

Abstract Anti-programmed cell death-1 (anti-PD-1) blockade in tumor therapy results in an expansion of CD8+ T cells and can restore the function of exhausted CD8+ T cells. We identified GSK-3 as a key upstream kinase of regulating PD-1 expression. Inhibition of GSK-3 in CD8+ T cells increased Tbx21 (Tbet), which suppressed Pdcd1 (PD-1) transcription (Taylor et al., Immunity 2016). In controlling spontaneous pulmonary metastasis of B16 melanoma and EL-4 lymphoma cells, GSK-3 blockade is as effective as anti-PD-1 blocking antibody (Taylor et al., Cancer Research 2018). Given the clinical importance in devising strategies to overcome tumor resistance to immune checkpoint blockade, we assessed whether the combined use of GSK-3 small-molecule inhibitor (SMI) and anti-PD-1 can overcome resistance to anti-PD-1 monotherapy. Indeed, GSK-3 SMI and anti-PD-1 synergized in therapy against solid B16 tumors that are resistant to monotherapy, leading to delayed tumor growth. Further, the synergy of GSK-3 SMI and anti-PD-1 therapy has been successfully confirmed by using adoptive transfer of OT1 cells into B16-OVA tumor-bearing mice. High-dimensional profiling of tumor-infiltrated lymphocytes (TILs) using mass cytometry (CyTOF) showed that the combination therapy gave an increase in cellularity of CD8+ effector memory T cells, which correlated to better tumor control. Transcriptome analysis of these CD8+ TILs highlighted the increased cytotoxicity as shown by significant changes of granzymes. Our findings outline a next-generation approach of potentiating PD-1 antibody therapy with SMIs of GSK-3 that synergizes as therapy by boosting the cellularity and cytotoxicity of tumor infiltrated CD8+ T cells. Citation Format: Janna Krueger, Alison Taylor, Alexandra Kazanova, Saloua Jeidane, Vinicius Motta, Ian Watson, Christopher E. Rudd. Inhibition of Glycogen Synthase Kinase 3 (GSK-3) synergizes with anti-PD-1 by potentiating tumor-infiltrated CD8+ T-cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A59.