MDSCs-derived GPR84 induces CD8⁺ T-cell senescence via p53 activation to suppress the antitumor response

Backgrounds: G-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how GPR84 endowed the stronger inhibition of MDSCs to CD8⁺ T cells function is not well established. In this study, we aimed to identify the underlying mechanism behind the immunosuppression of CD8⁺ T cells by GPR84⁺ MDSCs.

Methods: The role and underlying mechanism that MDSCs or exosomes (Exo) regulates the function of CD8⁺ T cells were investigated using immunofluorescence, fluorescence activating cell sorter (FACS), quantitative real-time PCR, western blot, ELISA, Confocal, RNA-sequencing (RNA-seq), etc. In vivo efficacy and mechanistic studies were conducted with wild type, GPR84 and p53 knockout C57/BL6 mice.

Results: Here, we showed that the transfer of GPR84 from MDSCs to CD8⁺ T cells via the Exo attenuated the antitumor response. This inhibitory effect was also observed in GPR84-overexpressed CD8⁺ T cells, whereas depleting GPR84 elevated CD8⁺ T cells proliferation and function in vitro and in vivo. RNA-seq analysis of CD8⁺ T cells demonstrated the activation of the p53 signaling pathway in CD8⁺ T cells treated with GPR84⁺ MDSCs culture medium. While knockout p53 did not induce senescence in CD8⁺ T cells treated with GPR84⁺ MDSCs. The per cent of GPR84⁺ CD8⁺ T cells work as a negative indicator for patients' prognosis and response to chemotherapy.

Conclusions: These data demonstrated that the transfer of GPR84 from MDSCs to CD8⁺ T cells induces T-cell senescence via the p53 signaling pathway, which could explain the strong immunosuppression of GPR84 endowed to MDSCs.