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

Cellular & Molecular Immunology volume 19, pages 516–526 (2022)Cite this article

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A Correction to this article was published on 13 May 2022

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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.

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Acknowledgements

This project was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-047 and 2019-I2M-5-049), National Science Funds of China (82073181, 81802870 and 82102371), Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT310-006, 2019XK310002 and 2018TX31001), as well as NIH R01AI069120, AI158154, and AI140718 grants, the UCLA AIDS Institute, and UCLA David Geffen School of Medicine–Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award Program. H.Y. is supported by science funds from Jiangsu Province (BK20211554, BK20170407) and the Innovative and Entrepreneurial Team grant (2018-2021) from Jiangsu Province. L.L. is supported by Innovative and Entrepreneurial Doctor grant (2020-2022) from Jiangsu Province.

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Author notes

  1. These authors contributed equally: Chaohu Pan, Qiaomei Cai.

Authors and Affiliations

  1. Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China

    Chaohu Pan, Yu Chen & Tianqi Sui

  2. Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China

    Chaohu Pan, Liping Yang, Yu Chen & Tianqi Sui

  3. Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China

    Qiaomei Cai, Xiaorong Li, Lili Li, Junxiao Liu, Wancheng Liu, Meiling Gao, Huiming Fan, Jiayin Ruan, Yueyue Shi & Heng Yang

  4. The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China

    Liping Yang

  5. Heze Vocational College, 274008, Heze, China

    Xiaoyang Wang

  6. Affiliated Tumor Hospital of Nantong University, 226000, Nantong, China

    Saihua Chen

  7. Department of Dermatology, University of Pittsburgh Medical Center, 3708 Fifth Avenue, Suite 500.68, Pittsburgh, PA, 15213, USA

    Lucy S. Cheng

  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

    Jiayong Liu

  9. Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    Genhong Cheng

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  1. Chaohu Pan
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Contributions

CP and QC contributed equally to this work. CP and QC performed the experiments. CP, XL, and LY analyzed data. CP, QC, YS, JR, LSC, HY and GC wrote the paper. QC, LL, LY, YC, JL, WL, MG, TS, XW, HF, and SC provided technical support. All authors have read and approved the final paper.

Corresponding authors

Correspondence to Jiayong Liu, Heng Yang or Genhong Cheng.

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Competing interests

HY and CH have filed a patent related to the anti-HSV-1 activity of BACH1.

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Pan, C., Cai, Q., Li, X. et al. Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1. Cell Mol Immunol 19, 516–526 (2022). https://doi.org/10.1038/s41423-021-00824-3

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