NK cell tumor therapy modulated by UV-inactivated oncolytic herpes simplex virus type 2 and checkpoint inhibitors

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Oncolytic virotherapy using oncolytic herpes simplex virus type 2 (oHSV2) is a promising cancer treatment strategy entering clinical trials.
• Natural killer (NK) cells are crucial for innate immunity against tumors, but their interactions with oHSV2 and effects on antitumor responses require further elucidation.
• The roles of activating surface receptors and checkpoint inhibitors on oHSV2-treated cells remain largely unknown.

Purpose of the Study:

• To investigate the effects of UV-inactivated oHSV2 (UV-oHSV2) on human peripheral blood mononuclear cells (PBMCs) and NK cell-mediated antitumor activity.
• To elucidate the molecular mechanisms underlying UV-oHSV2-induced NK cell activation and antitumor functions.
• To explore the impact of UV-oHSV2 on immune checkpoint molecules NKG2A and HLA-E and evaluate combination therapy potential.

Main Methods:

• Treatment of human PBMCs and NK92 cells with UV-oHSV2.
• Assessment of NK cell activation, cytokine release (IFN-γ), and cytotoxicity in vitro and in vivo.
• Analysis of Toll-like receptor 2 (TLR2)/NF-κB signaling pathway activation.
• Evaluation of NKG2A and HLA-E expression and the effects of blocking antibodies.

Main Results:

• UV-oHSV2 significantly enhances antitumor activity of PBMCs and NK cells in vitro and in vivo.
• UV-oHSV2-stimulated NK cells release IFN-γ via the TLR2/NF-κB signaling pathway, mediating antitumor effects through TLR2.
• UV-oHSV2 upregulates NKG2A on NK cells and HLA-E on tumor cells, and blocking these checkpoints potentiates UV-oHSV2-induced antitumor effects.

Conclusions:

• UV-inactivated oHSV2 is a potent activator of NK cells, enhancing their antitumor functions through TLR2 signaling.
• UV-oHSV2 modulates the NKG2A/HLA-E immune checkpoint pathway, presenting a novel therapeutic target.
• Combination therapy of oHSV2 with anti-NKG2A and anti-HLA-E antibodies holds synergistic potential for future cancer treatment.