Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
J Immunother Cancer. 2023 Nov 28;11(11):e007802. doi: 10.1136/jitc-2023-007802.
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.
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.
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.
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.
G 蛋白偶联受体 84（GPR84）标记了肿瘤微环境中具有更强免疫抑制作用的髓系来源抑制细胞（MDSC）的一个亚群。然而，GPR84 如何赋予 MDSC 对 CD8 T 细胞功能更强的抑制作用尚不清楚。在这项研究中，我们旨在确定 GPR84 MDSC 对 CD8 T 细胞免疫抑制的潜在机制。
使用免疫荧光、荧光激活细胞分选（FACS）、实时定量 PCR、Western blot、ELISA、共聚焦、RNA 测序（RNA-seq）等方法研究了 MDSC 或外泌体（Exo）调节 CD8 T 细胞功能的作用和潜在机制。使用野生型、GPR84 和 p53 敲除 C57/BL6 小鼠进行体内疗效和机制研究。
在这里，我们表明 MDSC 通过 Exo 将 GPR84 转移到 CD8 T 细胞中会减弱抗肿瘤反应。在 GPR84 过表达的 CD8 T 细胞中也观察到这种抑制作用，而耗尽 GPR84 则会增加 CD8 T 细胞在体外和体内的增殖和功能。对 CD8 T 细胞进行 RNA-seq 分析表明，在 GPR84 MDSC 培养物处理的 CD8 T 细胞中激活了 p53 信号通路。然而，敲除 p53 不会诱导 GPR84 MDSC 处理的 CD8 T 细胞衰老。GPR84 CD8 T 细胞的比例可作为患者预后和对化疗反应的负性指标。
这些数据表明，GPR84 从 MDSC 转移到 CD8 T 细胞会通过 p53 信号通路诱导 T 细胞衰老，这可以解释 GPR84 赋予 MDSC 的强大免疫抑制作用。
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