Abstract
The serine/threonine kinase, glycogen synthase kinase 3 (GSK-3) has been implicated in immune cell activation and function. Our recent studies have shown that the abrogation of GSK-3 activity down-regulates the expression of key inhibitory receptors PD-1 and LAG-3. It also regulates the expression of the transcription factor NFAT which, in turn, is responsible for inhibiting PD-1/LAG-3 transcription as well as activating the expression of cytolytic effector proteins such as perforin and granzyme B. The role of components of the Wnt signaling pathway in these events remains to be fully uncovered. This mini-review discusses the recent discoveries that have elucidated the role of the GSK-3 signaling pathway in cancer immunotherapy.
Highlights
While the immune system is capable of recognizing tumor antigens, certain cancer cells evade immune detection and destruction [1]
The tumor microenvironment can create conditions that limit the immune response by impairing antigen presentation, releasing immunosuppressive cytokines, exhausting the availability of oxygen and nutrients, and promoting the recruitment of immunosuppressive regulatory T-cells (Tregs), neutrophils and myeloid derived suppressor cells (MDSCs) [1,3]
As in the case of classic peptide antigen presentation, tumor neoantigens can be presented by major histocompatibility complexes I and II (MHC-I and MHC-II) leading to T-cell activation [3,4]. This involves the engagement of the receptor (TCR) and coreceptors, CD4 and CD8 which we showed bind to the protein-tyrosine kinase p56lck (LCK)
Summary
While the immune system is capable of recognizing tumor antigens, certain cancer cells evade immune detection and destruction [1]. ZAP-70 phosphorylates immune cell adaptor proteins, linker of activated T-cells (LAT) and the SH2-domain containing signal transducing adaptor protein (SLP-76) [11,12]. Phosphorylated LAT serves as a docking site for SLP-76, leading to T-cell activation, proliferation, differentiation, and cytokine release.
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