Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Department of Medicine-Division of Hematology/Oncology, Feinberg School of Medicine Northwestern University, Chicago, IL, 60611, USA.
Signal Transduct Target Ther. 2023 Apr 28;8(1):164. doi: 10.1038/s41392-023-01388-6.
Myeloid-derived suppressor cells (MDSCs) were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression. Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored, currently, there are still no effective means for targeting MDSCs clinically. The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic. This study identified that GPR84 was exclusively overexpressed on MDSCs. It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models, which drives the immunosuppression on CD8T cells by inhibiting PD-L1 degradation in lysosomes. Furthermore, G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβ signaling pathway. In addition, GPR84MDSCs and PD-L1MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer, and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment. Finally, GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses. Therefore, targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors. This combination therapy has the potential for tumor therapy in clinics.
髓源抑制性细胞（MDSCs）在肿瘤进展过程中逐渐在原位食管癌小鼠模型中积累。虽然 MDSCs 促进肿瘤生长和抑制免疫反应的作用已被广泛研究，但目前临床上仍没有针对 MDSCs 的有效靶向手段。MDSCs 缺乏特异性标志物是临床上消除 MDSCs 策略有限的原因。本研究鉴定出 GPR84 仅在 MDSCs 上过度表达。进一步发现，GPR84 在临床样本和肿瘤小鼠模型中的 MDSCs 上显著表达，通过抑制溶酶体中的 PD-L1 降解来驱动 CD8T 细胞的免疫抑制。此外，G-CSF 和 GM-CSF 通过 STAT3/C/EBPβ 信号通路诱导 GPR84 表达。此外，GPR84MDSCs 和 PD-L1MDSCs 在抗 PD-1 治疗耐药的食管癌患者中高度积累，并且高 GPR84 特征风险被验证为抗 PD-1 治疗患者总生存期的负面因素。最后，GPR84 拮抗作用联合抗 PD-1 抗体增强了抗肿瘤反应。因此，靶向 GPR84 增强了食管癌和其他恶性肿瘤的抗 PD-1 疗效。这种联合治疗有可能在临床上用于肿瘤治疗。
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