A novel HVEM-Fc recombinant protein for lung cancer immunotherapy.

Abstract

Background: The ubiquitously expressed transmembrane protein, Herpesvirus Entry Mediator (HVEM), functions as a molecular switch, capable of both activating and inhibiting the immune response depending on its interacting ligands. HVEM-Fc is a novel recombinant fusion protein with the potential to eradicate tumor cells.

Methods: The anti-tumor efficacy of HVEM-Fc was evaluated in C57BL/6 mice-bearing lung cancer models: a syngeneic model and an orthotopic model of mouse lung cancer. Additionally, patient-derived organoids were employed in conjunction with T cell co-culture systems. To investigate the underlying mechanisms, a comprehensive array of techniques was utilized, including single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and flow cytometry. Furthermore, the anti-tumor effects of HVEM-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed. Finally, mouse immune cell depletion antibodies were used to elucidate the underlying mechanisms of action.

Results: In vivo, 1 mg/kg HVEM-Fc demonstrated effective inhibition of tumor growth and metastasis in C57BL/6 mice bearing lung cancer model and a KP orthotopic model of mouse lung cancer. Multi-omics analysis showed that HVEM-Fc induced an immune-stimulatory microenvironment. Notably, the combination of HVEM-Fc with a PD-1 inhibitor demonstrated the most potent inhibition of tumor cell growth. In vitro, HVEM-Fc was validated to eradicate tumor cells through the activation of T cells in both non-small cell lung cancer (NSCLC) organoids and T cell co-culture models.

Conclusions: Our data demonstrate that HVEM-Fc exerts a strong signal that augments and prolongs T-cell activity in both murine models and human NSCLC organoid models. Moreover, the combination of HVEM-Fc with a PD-1 inhibitor yields the most effective anti-tumor outcomes.