HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

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Abstract

The incidence of human papillomavirus–positive (HPV ⁺) head and neck squamous cell carcinoma (HNSCC) has surpassed that of cervical cancer and is projected to increase rapidly until 2060. The coevolution of HPV with transforming epithelial cells leads to the shutdown of host immune detection. Targeting proximal viral nucleic acid–sensing machinery is an evolutionarily conserved strategy among viruses to enable immune evasion. However, E7 from the dominant HPV subtype 16 in HNSCC shares low homology with HPV18 E7, which was shown to inhibit the STING DNA-sensing pathway. The mechanisms by which HPV16 suppresses STING remain unknown. Recently, we characterized the role of the STING/type I interferon (IFN-I) pathway in maintaining immunogenicity of HNSCC in mouse models. Here we extended those findings into the clinical domain using tissue microarrays and machine learning–enhanced profiling of STING signatures with immune subsets. We additionally showed that HPV16 E7 uses mechanisms distinct from those used by HPV18 E7 to antagonize the STING pathway. We identified NLRX1 as a critical intermediary partner to facilitate HPV16 E7–potentiated STING turnover. The depletion of NLRX1 resulted in significantly improved IFN-I–dependent T cell infiltration profiles and tumor control. Overall, we discovered a unique HPV16 viral strategy to thwart host innate immune detection that can be further exploited to restore cancer immunogenicity.

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Most cited references 31

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STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

Seng-Ryong Woo, Mercedes Fuertes, Leticia Corrales … (2014)

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

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Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma

Maura L. Gillison, Anil Chaturvedi, William F Anderson … (2015)

Human papillomavirus (HPV) is now established as the principal cause of an increase in incidence of a subset of head and neck squamous cell cancers (HNCs) in numerous geographic regions around the world. Further study of the epidemiology of HPV-positive HNC will be critical to the development and implementation of public health interventions to reverse these global incidence trends. Here, recent data are reviewed to provide insight into several topics, including incidence trends and projections for HPV-positive HNC; the worldwide HPV-attributable fraction; sex disparities in cancer risk; the epidemiology of oral HPV infection; the latency period between infection and cancer; the potential impact of prophylactic HPV vaccination; and prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The identification of a single necessary cause for any cancer provides a rare and perhaps extraordinary opportunity for cancer prevention.

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The Atg5 Atg12 conjugate associates with innate antiviral immune responses.

Nao Jounai, Fumihiko Takeshita, Kouji Kobiyama … (2007)

Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5-Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5'-phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7-deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA-mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells.

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Author and article information

Contributors

Xiaobo Luo

Christopher R. Donnelly

Wang Gong

Blake R. Heath

Yuning Hao

Lorenza A. Donnelly:

ORCID: http://orcid.org/0000-0001-5377-8842

Toktam Moghbeli

Yee Sun Tan

Xin Lin

Emily Bellile:

ORCID: http://orcid.org/0000-0003-4350-4658

Benjamin A. Kansy:

ORCID: http://orcid.org/0000-0001-5934-5618

Thomas E. Carey

J. Chad Brenner

Lei Cheng:

ORCID: http://orcid.org/0000-0002-2762-4740

Peter J. Polverini:

ORCID: http://orcid.org/0000-0001-9832-967X

Meredith A. Morgan

Haitao Wen:

ORCID: http://orcid.org/0000-0002-6363-2748

Mark E. Prince

Robert L. Ferris

Yuying Xie

Simon Young:

ORCID: http://orcid.org/0000-0002-8198-7083

Gregory T. Wolf

Qianming Chen

Yu L. Lei:

ORCID: http://orcid.org/0000-0002-9868-9824

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J. Clin. Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date Created: 24 February 2020

Publication date Created: 1 April 2020

Publication date PMC-release: 1 July 2020

Volume: 130

Issue: 4

Pages: 1635-1652

Affiliations

[1 ]Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

[2 ]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.

[3 ]Oral Health Sciences PhD Program, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

[4 ]Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

[5 ]Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing, Michigan, USA.

[6 ]University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.

[7 ]Department of Otolaryngology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany.

[8 ]Department of Otolaryngology–Head and Neck Surgery,

[9 ]Department of Pathology, and

[10 ]Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan, USA.

[11 ]Department of Microbial Infection and Immunity, Ohio State University College of Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

[12 ]Department of Otolaryngology, Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

[13 ]Department of Oral & Maxillofacial Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Author notes

Address correspondence to: Yu L. Lei, Department of Periodontics and Oral Medicine, Rogel Cancer Center, University of Michigan, 1600 Huron Parkway 2355, Ann Arbor, Michigan 48109, USA. Phone: 734.615.6967; Email: leiyuleo@ 123456umich.edu . Or to: Qianming Chen, West China School of Stomatology, Sichuan University, Renmin Nan Street Section 3 #14, Chengdu, Sichuan 610041, China. Phone: 86.28.85509709; Email: qmchen@ 123456scu.edu.cn .