HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING
Xiaobo Luo, Christopher R. Donnelly, Wang Gong, Blake R. Heath, Yuning Hao, Lorenza A. Donnelly, Toktam Moghbeli, Yee Sun Tan, Xin Lin, Emily Bellile, Benjamin A. Kansy, Thomas E. Carey, J. Chad Brenner, Lei Cheng, Peter J. Polverini, Meredith A. Morgan, Haitao Wen, Mark E. Prince, Robert L. Ferris, Yuying Xie, Simon Young, Gregory T. Wolf, Qianming Chen, Yu L. Lei
Xiaobo Luo, Christopher R. Donnelly, Wang Gong, Blake R. Heath, Yuning Hao, Lorenza A. Donnelly, Toktam Moghbeli, Yee Sun Tan, Xin Lin, Emily Bellile, Benjamin A. Kansy, Thomas E. Carey, J. Chad Brenner, Lei Cheng, Peter J. Polverini, Meredith A. Morgan, Haitao Wen, Mark E. Prince, Robert L. Ferris, Yuying Xie, Simon Young, Gregory T. Wolf, Qianming Chen, Yu L. Lei
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Research Article Immunology Oncology

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

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.

Authors

Xiaobo Luo, Christopher R. Donnelly, Wang Gong, Blake R. Heath, Yuning Hao, Lorenza A. Donnelly, Toktam Moghbeli, Yee Sun Tan, Xin Lin, Emily Bellile, Benjamin A. Kansy, Thomas E. Carey, J. Chad Brenner, Lei Cheng, Peter J. Polverini, Meredith A. Morgan, Haitao Wen, Mark E. Prince, Robert L. Ferris, Yuying Xie, Simon Young, Gregory T. Wolf, Qianming Chen, Yu L. Lei

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Figure 6

HPV16 E7 specifically interacts with NLRX1.

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HPV16 E7 specifically interacts with NLRX1. (A and B) 93VU147T and SCC90...
(A and B) 93VU147T and SCC90 cells were lysed, precleared, and incubated with an isotype control antibody and anti-HPV16 E7. Immunoprecipitation was performed using Protein A/G UltraLink Resin, and immunoprecipitated protein complexes were washed before SDS-PAGE. Immunoblotting of NLRX1 and specificity control proteins was carried out. (C) The whole-cell lysates of HPV18 E7–expressing UMSCC49 cells were precleared and incubated with IgG2a isotype control or anti–HPV18 E7, followed by incubation with Protein A/G UltraLink Resin for 2 hours at room temperature. Immunoprecipitated protein complexes were washed and subjected to SDS-PAGE. Immunoblotting of STING and specificity control proteins was performed. Experiments were performed 3 times, and representative results are shown. (D) 93VU147T cells were stained with MitoTracker, followed by fixation, permeabilization, and staining with NLRX1 and HPV16 E7. Nuclei were counterstained with Hoechst. Representative images and colocalization overlay are shown (scale bars: 10 μm). Experiments were performed twice.