Roles of GSK-3α and GSK-3β in T cell-mediated tumour rejection 3299

Abstract Description Glycogen synthase kinase-3 (GSK-3) has been shown as an upstream regulator of programmed cell death protein 1 (PD-1) and Lymphocyte activation gene-3 (LAG-3) gene expression in CD8 T cells and its inhibition can suppress tumour growth. However, the relative roles of the individual isoforms of GSK-3: a and b, in the modulation of PD-1 and protective immunity against cancer are yet to be elucidated. Here, we have generated individual a and b isoform-specific conditional KO (cKO) mice, resulting in mice with T cells devoid of either isoform. In vivo tumour models, have shown both isoforms to contribute to T cell function to different degrees. Interestingly, the loss of either isoform increased expression of the transcription factor Tbet, however, optimal reduction of PD-1 expression required the depletion of both isoforms. GSK-3b cKO mice were able to limit solid tumour growth to the same degree as GSK-3a/b cKO mice, pointing to a dominate role for GSK-3b in regulating tumour growth. However, depletion of the alpha isoform alone offered higher protection against intracranial tumours, which surpassed the impact of knocking out either the beta isoform alone or both isoforms. Both isoforms were found to have differential effects on IFNg and GZMB expression, while operating in synergy to reduce PD-1 expression and promote the infiltration of tumours with CD4 and CD8 T cells. Overall, our data suggests a complex interplay between the two isoforms in the control of tumour immunity. Funding Sources Supported by MRC MR/V033336/1 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)