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

Abstract

BACKGROUND:

In 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.

METHODS:

We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.

RESULTS:

We identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.

CONCLUSIONS:

Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

• Authors: Chaohu Pan, Qiaomei Cai, Xiaorong Li, Lili Li, Liping Yang, Yu Chen, Junxiao Liu, Wancheng Liu, Meiling Gao, Tianqi Sui, Xiaoyang Wang, Huiming Fan, Jiayin Ruan, Yueyue Shi, Saihua Chen, Lucy S Cheng, Jiayong Liu, Heng Yang, Genhong Cheng
• Journal: Cellular & molecular immunology (Cell Mol Immunol) Vol. 19 Issue 4 Pg. 516-526 (04 2022) ISSN: 2042-0226 [Electronic] China
• PMID: 34983952 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to CSI and USTC.

Chemical References

• Bach1 protein, mouse
• Basic-Leucine Zipper Transcription Factors

Topics

• Animals
• Basic-Leucine Zipper Transcription Factors (genetics)
• Herpesvirus 1, Human
• Immunity
• Melanoma
• Mice
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics)
• United States