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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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References

  1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    Article  CAS  PubMed  Google Scholar 

  3. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.

    Article  CAS  PubMed  Google Scholar 

  4. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

    Article  CAS  PubMed  Google Scholar 

  5. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  6. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.

    Article  CAS  PubMed  Google Scholar 

  7. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin CZ, Xiang GL, Zhu XH, Xiu LL, Sun JX, Zhang XY. Advances in the mechanisms of action of cancer-targeting oncolytic viruses. Oncol Lett. 2018;15:4053–60.

    PubMed  PubMed Central  Google Scholar 

  10. van Vloten JP, Workenhe ST, Wootton SK, Mossman KL, Bridle BW. Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies. J Immunol. 2018;200:450–8.

    Article  PubMed  CAS  Google Scholar 

  11. Russell SJ, Barber GN. Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines. Cancer Cell. 2018;33:599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng M, Huang J, Tong A, Yang H. Oncolytic viruses for cancer therapy: barriers and recent advances. Mol Ther Oncolytics. 2019;15:234–47.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ledford H. Cancer-fighting viruses win approval. Nature. 2015;526:622–3.

    Article  CAS  PubMed  Google Scholar 

  14. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2010;17:718–30.

    Article  PubMed  Google Scholar 

  15. Liu BL, Robinson M, Han ZQ, Branston RH, English C, Reay P, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10:292–303.

    Article  CAS  PubMed  Google Scholar 

  16. Andtbacka RH, Ross M, Puzanov I, Milhem M, Collichio F, Delman KA, et al. Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. Ann Surg Oncol. 2016;23:4169–77.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33:2780–8.

    Article  CAS  PubMed  Google Scholar 

  18. Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008;8:559–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol. 2011;1:519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472:481–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu SY, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity. 2013;38:92–105.

    Article  PubMed  CAS  Google Scholar 

  22. Smith S, Weston S, Kellam P, Marsh M. IFITM proteins-cellular inhibitors of viral entry. Curr Opin Virol. 2014;4:71–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li L, Zhao H, Liu P, Li C, Quanquin N, Ji X, et al. PARP12 suppresses Zika virus infection through PARP-dependent degradation of NS1 and NS3 viral proteins. Sci Signal. 2018;11:eaas9332.

  24. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008;451:425–30.

    Article  CAS  PubMed  Google Scholar 

  25. Ru J, Sun H, Fan H, Wang C, Li Y, Liu M, Tang H. MiR-23a facilitates the replication of HSV-1 through the suppression of interferon regulatory factor 1. PLoS ONE. 2014;9:e114021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol. 1996;16:6083–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang X, Guo J, Wei X, Niu C, Jia M, Li Q, Meng D. Bach1: function, regulation, and involvement in disease. Oxid Med Cell Longev. 2018;2018:1347969.

    PubMed  PubMed Central  Google Scholar 

  28. Hira S, Tomita T, Matsui T, Igarashi K, Ikeda-Saito M. Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure. IUBMB Life. 2007;59:542–51.

    Article  CAS  PubMed  Google Scholar 

  29. Nishizawa H, Matsumoto M, Shindo T, Saigusa D, Kato H, Suzuki K, Sato M, Ishii Y, Shimokawa H, Igarashi K. Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1. J Biol Chem. 2020;295:69–82.

    Article  CAS  PubMed  Google Scholar 

  30. Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, et al. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis. Cell. 2019;178:330–45 e322.

    Article  CAS  PubMed  Google Scholar 

  31. Lee J, Yesilkanal AE, Wynne JP, Frankenberger C, Liu J, Yan J, et al. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature. 2019;568:254–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Anderson NM, Simon MC. BACH1 Orchestrates Lung Cancer Metastasis. Cell. 2019;179:800.

    Article  CAS  PubMed  Google Scholar 

  33. Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, Tokunaga F, Iwai K, Igarashi K. Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol. 2007;27:6962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu SY, Sanchez DJ, Aliyari R, Lu S, Cheng G. Systematic identification of type I and type II interferon-induced antiviral factors. Proc Natl Acad Sci USA. 2012;109:4239–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Y, Wang S, Zhu H, Zheng C. Cloning of the herpes simplex virus type 1 genome as a novel luciferase-tagged infectious bacterial artificial chromosome. Arch Virol. 2011;156:2267–72.

    Article  CAS  PubMed  Google Scholar 

  36. Kitamuro T, Takahashi K, Ogawa K, Udono-Fujimori R, Takeda K, Furuyama K, et al. Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J Biol Chem. 2003;278:9125–33.

    Article  CAS  PubMed  Google Scholar 

  37. Moesta AK, Cooke K, Piasecki J, Mitchell P, Rottman JB, Fitzgerald K, et al. Local Delivery of OncoVEX(mGM-CSF) Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade. Clin Cancer Res. 2017;23:6190–202.

    Article  CAS  PubMed  Google Scholar 

  38. van Akkooi ACJ, Haferkamp S, Papa S, Franke V, Pinter A, Weishaupt C, et al. A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB-IVM1a Melanoma in Four European Countries. Adv Ther. 2021;38:1245–62.

    Article  PubMed  Google Scholar 

  39. Stahlie EHA, Franke V, Zuur CL, Klop WMC, van der Hiel B, Van de Wiel BA, Wouters M, Schrage YM, van Houdt WJ, van Akkooi ACJ. T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model. Cancer Immunol Immunother. 2021;70:2291–300.

    Article  CAS  PubMed  Google Scholar 

  40. Barral PM, Sarkar D, Su ZZ, Barber GN, DeSalle R, Racaniello VR, Fisher PB. Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharm Ther. 2009;124:219–34.

    Article  CAS  Google Scholar 

  41. Manivanh R, Mehrbach J, Knipe DM, Leib DA. Role of Herpes Simplex Virus 1 gamma34.5 in the Regulation of IRF3 Signaling. J Virol. 2017;91:e01156–17.

  42. Schwertner B, Lindner G, Toledo Stauner C, Klapproth E, Magnus C, Rohrhofer A, et al. Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo. Cancers (Basel). 2021;13:3058.

  43. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170:1109–19 e1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18:498–513.

    Article  CAS  PubMed  Google Scholar 

  45. Suzuki H, Tashiro S, Hira S, Sun J, Yamazaki C, Zenke Y, Ikeda-Saito M, Yoshida M, Igarashi K. Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J. 2004;23:2544–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xing J, Wang S, Lin F, Pan W, Hu CD, Zheng C. Comprehensive characterization of interaction complexes of herpes simplex virus type 1 ICP22, UL3, UL4, and UL20.5. J Virol. 2011;85:1881–6.

    Article  CAS  PubMed  Google Scholar 

  47. Sun HS, Hsiao KY, Hsu CC, Wu MH, Tsai SJ. Transactivation of steroidogenic acute regulatory protein in human endometriotic stromalcells is mediated by the prostaglandin EP2 receptor. Endocrinology. 2003;144:3934–42.

    Article  CAS  PubMed  Google Scholar 

  48. Chen KF, Lai YY, Sun HS, Tsai SJ. Transcriptional repression of human cad gene by hypoxia inducible factor-1alpha. Nucleic Acids Res. 2005;33:5190–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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