2. Academic Validation
  3. Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1

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

  • Cell Mol Immunol. 2022 Apr;19(4):516-526. doi: 10.1038/s41423-021-00824-3.
Chaohu Pan  # 1 2,  Qiaomei Cai  # 3,  Xiaorong Li 3,  Lili Li 3,  Liping Yang 2 4,  Yu Chen 1 2,  Junxiao Liu 3,  Wancheng Liu 3,  Meiling Gao 3,  Tianqi Sui 1 2,  Xiaoyang Wang 5,  Huiming Fan 3,  Jiayin Ruan 3,  Yueyue Shi 3,  Saihua Chen 6,  Lucy S Cheng 7,  Jiayong Liu 8,  Heng Yang 9,  Genhong Cheng 10
Affiliations

Affiliations

  • 1 Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China.
  • 2 Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China.
  • 3 Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China.
  • 4 The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
  • 5 Heze Vocational College, 274008, Heze, China.
  • 6 Affiliated Tumor Hospital of Nantong University, 226000, Nantong, China.
  • 7 Department of Dermatology, University of Pittsburgh Medical Center, 3708 Fifth Avenue, Suite 500.68, Pittsburgh, PA, 15213, USA.
  • 8 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, 52 Fucheng Rd, 100142, Beijing, China. [email protected].
  • 9 Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China. [email protected].
  • 10 Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA. [email protected].
  • # Contributed equally.
PMID: 34983952 DOI: 10.1038/s41423-021-00824-3
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.

Keywords

Antitumor immunity; Bach1; HSV-1; Hemin; IFN stimulated genes.

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