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J Clin Invest. 2020 Apr 1;130(4):1635-1652. doi: 10.1172/JCI129497.

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

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Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Oral Health Sciences PhD Program, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing, Michigan, USA.
University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.
Department of Otolaryngology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany.
Department of Otolaryngology-Head and Neck Surgery.
Department of Pathology, and.
Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan, USA.
Department of Microbial Infection and Immunity, Ohio State University College of Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Department of Otolaryngology, Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Oral & Maxillofacial Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA.


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.


Autophagy; Head and neck cancer; Immunology; Innate immunity; Oncology

[Available on 2020-07-01]
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