Kinome and Phosphor-proteome Dynamics of TCR/PD-1 Signalling and Strategies of Blocking PD-1 Signaling for Novel Immunotherapy
Abstract
The treatment of tumours remains challenge, necessitating the exploration of novel therapeutic strategies. This study aims to elucidate the mechanism of T cell immune response and tumour immune evasion, as well as the development of novel mechanism-informed therapeutic strategies. The research encompasses various aspects, including the suppression mechanisms of PD-1 on T cell signalling, investigating the role of kinases, particularly LCK, in PD-1 mediated T cell suppression, and the development of peptide-based inhibitors targeting the PD-1/PD-L1 interaction.
Central to this study is the elucidation of PD-1's role in suppressing T cell function. Employing a co-culture system with T cells and antigen presenting cells, the study integrated TMT-16plex mass spectrometry and SILAC labeling to examine the kinome and phosphoproteome dynamics of T cell signalling. The results provide a detailed perspective on the dynamic interaction of signalling pathways involved in T cell activation and inhibition, underscoring the crucial function of LCK in the PD-1 mediated suppression of T cells. Additionally, the dual role of LCK in influencing both the stimulatory and inhibitory pathways in T cells is corroborated through the examination of protein-protein interactions, using LCK knockdown cell lines and a T cell depletion mouse model. Lastly, the study explores the development of peptide-based inhibitors to block the PD-1 signalling, demonstrate favorable blocking efficiency and therapeutic potential in syngeneic mouse tumour models.
Overall, this comprehensive study promotes the understanding of T cell biology in cancer immunity, and further implies the novel immunotherapeutic strategies targeting key regulators in the PD-1 signalling pathway.