PKR induces TGF-β and limits oncolytic immune therapy

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Mammalian cells possess intracellular antiviral defense mechanisms like RNA-activated protein kinase (PKR), cGAS-STING, and TLR-MyD88.
• PKR is identified as a significant barrier to oncolytic herpes simplex virus (oHSV) replication in vitro.

Purpose of the Study:

• To investigate the role of PKR in host responses to oncolytic virotherapy.
• To develop and evaluate a novel oHSV engineered to disable PKR signaling in tumor cells (oHSV-shPKR).

Main Methods:

• Generation of oHSV-shPKR to target tumor intrinsic PKR signaling.
• In vitro and in vivo experiments assessing viral replication, tumor cell lysis, and immune responses.
• Single-cell RNA sequencing and cell-cell communication analysis.
• Evaluation of oHSV-shPKR in murine models of glioblastoma.

Main Results:

• oHSV-shPKR suppressed innate antiviral immunity, enhancing viral spread and tumor cell lysis.
• PKR activation correlated with TGF-ß immune suppressive signaling.
• PKR-targeting oHSV modulated the tumor immune microenvironment, increasing antigen presentation and CD8 T cell activity.
• Single intratumoral injection of oHSV-shPKR significantly improved survival in mice with orthotopic glioblastoma.

Conclusions:

• PKR has dual roles: activating antiviral innate immunity but also inducing TGF-ß signaling that inhibits antitumor adaptive immunity.
• PKR is a critical target (Achilles' heel) for oHSV therapy, limiting both viral replication and anti-tumor immunity.
• An oHSV engineered to target PKR significantly enhances virotherapy response and improves outcomes in glioblastoma models.