Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma

Area of Science:

• Neuro-oncology
• Immunotherapy
• Virology

Background:

• Oncolytic viruses (oHSVs) trigger local tumor destruction and inflammation, but their ability to overcome immunosuppression in non-infected tumor regions remains unclear.
• Glioblastoma (IDH wild-type) is a highly aggressive brain tumor characterized by diffuse infiltration and significant macrophage-dominant immunosuppression.

Purpose of the Study:

• To investigate the immunologic effects of oHSVs in a genetically engineered mouse model of IDH wild-type glioblastoma.
• To determine if oHSVs can induce abscopal effects and overcome tumor immunosuppression in distant, non-infected areas.

Main Methods:

• Utilized a genetically engineered mouse model of IDH wild-type glioblastoma.
• Administered oHSV armed with a UL16-binding protein 3 (ULBP3) expression cassette.
• Evaluated tumor growth, immune cell infiltration (macrophages, T cells), and gene expression profiles.
• Assessed the synergistic effects of oHSV-ULBP3 with anti-programmed cell death 1 (anti-PD-1) therapy.

Main Results:

• Infection with oHSV-ULBP3 inhibited distant tumor growth (abscopal effect) without viral spreading, leading to activated macrophage and T cell accumulation.
• oHSV-ULBP3 demonstrated abscopal synergism with anti-PD-1 therapy against distant tumor areas; anti-PD-1 monotherapy was ineffective.
• ULBP3-armed oHSV upregulated antigen processing and presentation gene sets in myeloid cells, suggesting a noncanonical mechanism involving myeloid cells.

Conclusions:

• oHSV-ULBP3 can induce a myeloid-dominant, anti-PD-1-sensitive abscopal effect in glioblastoma, potentially overcoming tumor immunosuppression.
• The findings warrant further investigation of oHSV-ULBP3 in clinical trials for patients with IDH wild-type glioblastoma.