Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.

Area of Science:

• Virology
• Immunology
• Cancer Therapy

Background:

• Herpes simplex virus 1 (HSV-1) oncolytic virus therapy shows promise but is limited by replication capacity and understanding of immune response.
• Talimogene laherparepvec (T-VEC), derived from HSV-1, was the first oncolytic virus approved for melanoma treatment.

Purpose of the Study:

• To investigate mechanisms regulating HSV-1 replication in cancer cells.
• To enhance the antitumor efficacy of HSV-1 by increasing its replication in tumor cells.

Main Methods:

• Systematic screening to identify interferon-stimulated genes (ISGs) affecting HSV-1 replication.
• Functional analysis of BACH1's role in HSV-1 replication and HSV-1-induced immunogenic cell death.
• In vivo studies using murine tumor models (MCA205 and B16) to evaluate BACH1 deficiency effects on HSV-1 antitumor activity.

Main Results:

• Identified eight ISGs that regulate HSV-1 replication, with BACH1 identified as a suppressor of viral replication by inhibiting key viral genes (ICP4, ICP27, UL39).
• Loss of BACH1 function increased HSV-1 proliferation, promoted virus-induced apoptosis, HMGB1 secretion, and calreticulin exposure.
• Hemin, a drug that downregulates BACH1, significantly enhanced HSV-1 antitumor activity and increased T lymphocyte infiltration in tumors.

Conclusions:

• Uncovered a novel antiviral role for BACH1, demonstrating its suppression of HSV-1 replication.
• Provided a new strategy to improve the clinical efficacy of HSV-1 as an oncolytic virus by targeting BACH1.