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

Abstract

BackgroundsG-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.MethodsThe 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.ResultsHere, 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.ConclusionsThese 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.

Exosomes target HBV-host interactions to remodel the hepatic immune microenvironment

“…Research has indicated that exosomal delivery of high levels of programmed death-ligand 1 (PD-L1) can lead to macrophage dysfunction, indirectly impairing T-cell function [ 95 ]. Additionally, exosomes from myeloid-derived suppressor cells (MDSCs) can induce T-cell senescence through the P53 pathway [ 96 ]. Therefore, we speculate that exosomes may be involved in delivering immunosuppressive cytokines, upregulating inhibitory receptors or ligands, and increasing the proportion of regulatory cells.…”

The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity

“…While the exact impact of cellular senescence within MDSCs has yet to be explored, these cells are highly associated with the onset of age-related immune changes by modulating senescence phenotypes in surrounding cells. For example, one study found that MDSCs prevent senescence in cardiac myofibroblasts, resulting in age-related cardiac fibrosis [124]. Another study demonstrated that a subpopulation of MDSCs could induce senescence in CD8+ T-cells through exosomal transfer of GPR84, a G-protein coupled receptor that signals through p53 to halt cell proliferation [125].…”