HVEM as a tumor-intrinsic regulator in non-small cell lung cancer: Suppression of metastasis via glycolysis inhibition and modulation of macrophage polarization

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.