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HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING
Xiaobo Luo, … , Qianming Chen, Yu L. Lei
Xiaobo Luo, … , Qianming Chen, Yu L. Lei
Published December 24, 2019
Citation Information: J Clin Invest. 2020;130(4):1635-1652. https://doi.org/10.1172/JCI129497.
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Research Article Immunology Oncology Article has an altmetric score of 34

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.

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 9

NLRX1-potentiated tumor immune escape is IFN-I–dependent.

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NLRX1-potentiated tumor immune escape is IFN-I–dependent.
(A) C57BL/6 ho...
(A) C57BL/6 hosts were given 0.5 mg of anti-CD8 or PBS intraperitoneally daily for 3 days before the tumor implantation and then twice per week for 2 weeks. The overall tumor burden was compared using the generalized estimating equations model (n = 7 in each group; *P < 0.05). (B) Tumors were harvested and total RNA isolated for qPCR detection of the indicated STING signature genes. Values represent mean ± SEM. Comparisons between groups were assessed using an unpaired t test. (C) One million EV control or shNLRX1 MOC2-E6/E7 cells were inoculated subcutaneously in the right flank of Rag1–/– mice. Tumors were monitored and compared as described above (n = 6 in each group). (D) After euthanasia, tumors were harvested and total RNA was isolated. qPCR was conducted to quantify the mRNA levels of indicated genes. Values represent mean ± SEM. Comparisons between groups were assessed using an unpaired t test. (E) One million EV control or shNLRX1 MOC2-E6/E7 cells were inoculated subcutaneously in the right flank of Ifnar1–/– mice (n = 5 in control group, n = 6 in shNLRX1 group). Tumor growth was monitored and compared as described above. Experiments were performed twice, and 1 representative set is shown. (F) After euthanasia, all tumors were harvested and total RNA isolated for qPCR analysis. Values represent mean ± SEM. Comparisons between groups were assessed using an unpaired t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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