髓系抑制细胞(MDSCs)对肿瘤的免疫逃逸起着重要作用，并已被确认为宫颈癌中的免疫抑制性细胞。TMPRSS11D (跨膜丝氨酸蛋白酶11D)在某些癌症中的作用已有报道，但其在宫颈癌免疫逃逸中的角色尚不清楚。本研究旨在阐明TMPRSS11D对宫颈癌MDSCs免疫抑制功能的调控机制。我们的数据显示，恶性宫颈癌患者外周血单个核细胞(PBMCs)中多形核粒细胞MDSCs (PMN-MDSCs)的比例、MDSCs分泌的免疫抑制因子(INOS、IDO和ARG-1)的含量以及TMPRSS11D mRNA水平均显著高于良性肿瘤患者。其次，将宫颈癌患者的PBMCs中的CD3+ T细胞经抗CD3和抗CD28刺激，然后与同一供体的PMN-MDSCs以1:2的比例共培养3天。来自恶性肿瘤的PMN-MDSCs产生的ROS较多，而TMPRSS11D沉默阻断了ROS的产生。PMN-MDSCs抑制T细胞的增殖和IFN-γ的产生，而沉默PMN-MDSCs中的TMPRSS11D则阻碍了PMN-MDSCs的免疫抑制效应。机制上，TMPRSS11D与ALR (肝再生增强剂)结合，并负调控ALR的表达，诱导PMN-MDSCs中的内质网应激，进而增强PMN-MDSCs对T细胞的免疫抑制效应。此外，进行了小鼠异种移植瘤实验，评估了TMPRSS11D在肿瘤生长和MDSCs在体内积累中的作用。沉默TMPRSS11D阻止了宫颈癌异种移植瘤的生长，并减少了瘤组织中MDSCs的积累。总之，TMPRSS11D通过负调控ALR在MDSCs中诱导内质网应激，从而增强MDSCs对T细胞的免疫抑制效应，促进宫颈癌肿瘤的生长。版权所有© 2023 Elsevier B.V. 保留所有权利。

Myeloid-derived suppressor cells (MDSCs) contribute to tumor immune evasion, and have been identified as immunosuppressive cells in cervical cancer. The effect of TMPRSS11D (transmembrane serine protease 11D) in some cancers has been reported, but its role in immune escape of cervical cancer is still unclear. This study aims to elucidate the regulatory mechanism of TMPRSS11D on the immunosuppressive function of MDSCs in cervical cancer. Our data showed that the proportion of polymorphonucleoid MDSCs (PMN-MDSCs), the contents of immunosuppressive factors (including INOS, IDO, and ARG-1) secreted by MDSCs, and TMPRSS11D mRNA level in peripheral blood mononuclear cells (PBMCs) of malignant cervical cancer patients was significantly higher than that of benign tumor patients. Next, CD3+ T cells from PBMCs of cervical cancer patients were stimulated with anti-CD3 and anti-CD28, and then co-cultured with PMN-MDSCs from the same donors at a ratio of 1:2 for 3 days. PMN-MDSCs from malignant tumors produced more ROS, while TMPRSS11D knockdown blocked ROS production. PMN-MDSCs inhibited T cell proliferation and IFN-γ production, while silencing TMPRSS11D in PMN-MDSCs hindered the immunosuppressive effect of PMN-MDSCs. Mechanistically, TMPRSS11D bound to ALR (Augmenter of liver regeneration) and negatively regulated ALR expression, inducing ER stress in PMN-MDSCs, thereby enhancing the immunosuppressive effect of PMN-MDSCs on T cells. Additionally, mouse xenograft tumor assay was conducted to assess the role of TMPRSS11D in tumor growth and MDSC accumulation in vivo. Silencing TMPRSS11D impeded the growth of cervical cancer xenografts and reduced the accumulation of MDSCs in tumor tissues. In conclusion, TMPRSS11D induced ER stress in MDSCs through negative regulation of ALR, thus enhancing the immunosuppressive effect of MDSCs on T cells, so as to promote the growth of cervical cancer tumors.Copyright © 2023 Elsevier B.V. All rights reserved.