Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy

Area of Science:

• Oncology
• Virology
• Immunotherapy

Background:

• Oncolytic herpes simplex-1 virus (oHSV) therapy is a promising cancer immunotherapy approved by the FDA.
• However, its efficacy is limited by tumor and tumor microenvironment (TME) resistance in many patients.

Purpose of the Study:

• To identify molecular targets contributing to oHSV resistance.
• To elucidate the mechanisms underlying resistance to oHSV therapy in glioma and breast cancer brain metastasis (BCBM) models.

Main Methods:

• RNA sequencing (RNA-Seq) was employed to identify resistance targets.
• Murine models of intracranial glioma and BCBM were used to study oHSV resistance mechanisms.

Main Results:

• IGF2 was identified as a key secreted protein upregulated post-oHSV treatment, also observed in recurrent GBM patients.
• Depleting IGF2 enhanced oHSV's tumor-killing ability and improved survival in vivo.
• A novel oHSV variant, oHSV-D11mt, secreting IGF2R domain 11 (IGF2RD11mt), effectively blocked IGF2, increasing cytotoxicity and enhancing anti-tumor immune responses.

Conclusions:

• This study is the first to report that secreted IGF2 plays a critical role in oHSV resistance.
• The novel oHSV-D11mt variant represents a promising therapeutic advance for overcoming oHSV resistance and enhancing viro-immunotherapy.