Yao Yuanshan, Li Bin, Chen Chunji, Wang Jing, Yao Feng, Li Zhigang
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Department of Thoracic Surgery, Huadong Hospital affiliated to Fudan University, Shanghai 200040, China.
Pharmacol Res. 2025 Mar;213:107604. doi: 10.1016/j.phrs.2025.107604. Epub 2025 Jan 18.
Herpes virus entry mediator (HVEM) is a novel costimulatory molecule which mediates stimulatory or inhibitory signals in immune responses which makes it an attractive target in cancer therapeutics. However, the role of tumor cell intrinsic HVEM on tumor biology remains largely unknown. In this study, We demonstrated that CK+HVEM+ tumor correlates with better survival using Multiplex immuno histochemistry (mIHC) in Human Lung Adenocarcinoma Tissue microarray. Next, we showed that HVEM knockdown promoted NSCLC cell invasion and metastasis in vitro whereas exhibited no effect on proliferation. Conversely, HVEM overexpression results in the opposite phenotype. Meanwhile, the conclusion were further confirmed in vivo experiment that overexpression of HVEM reduced the invasion and metastasis of NSCLC whereas no effect on tumor mass. Besides, vivo experiment showed that M1 TAMs in the HVEM overxrpression group was increased and the proportion of M2 macrophages was decreased compared to the vector group. Mechanistically, The C-terminal 228-283 amino acid segment of HVEM protein interacts with the N-terminal 1-383 amino acid segment of MPRIP protein, inhibiting its downstream glycolysis signaling pathway and suppressing NSCLC cells progression. In addition, macrophage coculture assay suggested that HVEM overexpression inhibited M2 macrophage polarization through GM-CSF/GM-CSFRα axis. In summary, our study has demonstrated that tumor cell intrinsic HVEM is a potential tumour metastasis suppressor, which may serve as a potential target for immunotherapy.
疱疹病毒进入介质（HVEM）是一种新型共刺激分子，它在免疫反应中介导刺激或抑制信号，这使其成为癌症治疗中有吸引力的靶点。然而，肿瘤细胞内源性HVEM在肿瘤生物学中的作用仍 largely未知。在本研究中，我们使用多重免疫组织化学（mIHC）在人肺腺癌组织芯片中证明，CK+HVEM+肿瘤与更好的生存率相关。接下来，我们表明，HVEM敲低促进了非小细胞肺癌（NSCLC）细胞在体外的侵袭和转移，而对增殖没有影响。相反，HVEM过表达导致相反的表型。同时，体内实验进一步证实了这一结论，即HVEM过表达减少了NSCLC的侵袭和转移，而对肿瘤大小没有影响。此外，体内实验表明，与载体组相比，HVEM过表达组中的M1肿瘤相关巨噬细胞（TAM）增加，M2巨噬细胞的比例降低。机制上，HVEM蛋白的C末端228 - 283氨基酸片段与MPRIP蛋白的N末端1 - 383氨基酸片段相互作用，抑制其下游糖酵解信号通路并抑制NSCLC细胞进展。此外，巨噬细胞共培养实验表明，HVEM过表达通过GM - CSF/GM - CSFRα轴抑制M2巨噬细胞极化。总之，我们的研究表明，肿瘤细胞内源性HVEM是一种潜在的肿瘤转移抑制因子，可能作为免疫治疗的潜在靶点。
