Chaohu Pan1,2, Qiaomei Cai3, Xiaorong Li3, Lili Li3, Liping Yang2,4, Yu Chen1,2, Junxiao Liu3, Wancheng Liu3, Meiling Gao3, Tianqi Sui1,2, Xiaoyang Wang5, Huiming Fan3, Jiayin Ruan3, Yueyue Shi3, Saihua Chen6, Lucy S Cheng7, Jiayong Liu8, Heng Yang9, Genhong Cheng10. 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. liujiayong_doc@163.com. 9. Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China. yhmyt@hotmail.com. 10. Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA. gcheng@mednet.ucla.edu.
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.
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: Jacob P van Vloten; Samuel T Workenhe; Sarah K Wootton; Karen L Mossman; Byram W Bridle Journal: J Immunol Date: 2018-01-15 Impact factor: 5.422
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Authors: Paul C Tumeh; Christina L Harview; Jennifer H Yearley; I Peter Shintaku; Emma J M Taylor; Lidia Robert; Bartosz Chmielowski; Marko Spasic; Gina Henry; Voicu Ciobanu; Alisha N West; Manuel Carmona; Christine Kivork; Elizabeth Seja; Grace Cherry; Antonio J Gutierrez; Tristan R Grogan; Christine Mateus; Gorana Tomasic; John A Glaspy; Ryan O Emerson; Harlan Robins; Robert H Pierce; David A Elashoff; Caroline Robert; Antoni Ribas Journal: Nature Date: 2014-11-27 Impact factor: 49.962