STING信号通路在HPV相关恶性肿瘤中的作用

doi:10.12280/gjfckx.20220376

摘要/Abstract

摘要：

干扰素基因刺激蛋白（stimulator of interferon genes，STING）信号通路作为天然免疫通路，可以被细胞内细菌或病毒DNA片段激活，通过一系列下游信号通路促进Ⅰ型干扰素生成，是机体抗肿瘤免疫的中心组成部分。已有研究发现部分人乳头瘤病毒（human papilloma virus，HPV）阳性肿瘤组织中STING的表达上调，且高表达的STING与肿瘤患者良好预后相关，在肿瘤组织中注射STING激动剂可以观察到肿瘤组织的消退。然而也有部分研究认为，HPV存在免疫逃逸，可以在转录水平上干扰STING信号通路以及其他天然免疫途径，促进STING表观遗传学沉默和自噬降解，从而形成肿瘤局部免疫抑制微环境，促进肿瘤生长。综述STING信号通路在HPV相关恶性肿瘤中的作用，并分析STING激动剂在HPV相关恶性肿瘤治疗中的潜在应用价值。

关键词: 干扰素类, 乳头状瘤病毒科, 肿瘤, 信号传导, 干扰素基因刺激蛋白

Abstract:

Stimulator of interferon genes (STING) signaling pathway is a natural immune pathway, which can be activated by bacterial or viral DNA fragments in cytoplasm to promote type I interferon production through a series of downstream signaling pathways. It is a central part of the human anti-tumor immunity. Previous studies have found that STING expression was up-regulated in some human papilloma virus (HPV)-positive tumor tissues, and high expression of STING was associated with a better prognosis of tumor patients. We could observed remarkable regression of tumor when injecting STING agonists into tumor tissues. However, other studies believe that the immune escape of HPV could interfere with STING signaling pathways and other natural immune pathways at the transcriptional level, promote epigenetic silencing and autophagy degradation of STING, thus creating an immunosuppressive microenvironment of tumor and promoting tumor growth. Herein we will systematically elaborate the role of STING signaling pathway in HPV-positive malignant tumors and analyze the potential therapeutic value of STING agonists in HPV-positive tumors.

Key words: Interferons, Papillomaviridae, Neoplasms, Signal transduction, Stimulator of interferon genes

张展, 刘朝晖. STING信号通路在HPV相关恶性肿瘤中的作用[J]. 国际妇产科学杂志, 2023, 50(1): 30-34.

ZHANG Zhan, LIU Zhao-hui. Role of STING Signaling Pathway in HPV-Related Malignant Tumors[J]. Journal of International Obstetrics and Gynecology, 2023, 50(1): 30-34.

参考文献 37

[1]	White MK, Pagano JS, Khalili K. Viruses and human cancers: a long road of discovery of molecular paradigms[J]. Clin Microbiol Rev, 2014, 27(3):463-481. doi: 10.1128/CMR.00124-13. doi: 10.1128/CMR.00124-13 pmid: 24982317
[2]	Shannon-Lowe C, Rickinson A. The Global Landscape of EBV-Associated Tumors[J]. Front Oncol, 2019, 9:713. doi: 10.3389/fonc.2019.00713. doi: 10.3389/fonc.2019.00713 pmid: 31448229
[3]	Guven-Maiorov E, Tsai CJ, Nussinov R. Oncoviruses Can Drive Cancer by Rewiring Signaling Pathways Through Interface Mimicry[J]. Front Oncol, 2019, 9:1236. doi: 10.3389/fonc.2019.01236. doi: 10.3389/fonc.2019.01236 pmid: 31803618
[4]	Dagenais-Lussier X, Loucif H, Murira A, et al. Sustained IFN-I Expression during Established Persistent Viral Infection: A "Bad Seed" for Protective Immunity[J]. Viruses, 2017, 10(1):12. doi: 10.3390/v10010012. doi: 10.3390/v10010012
[5]	Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity[J]. Nature, 2009, 461(7265):788-792. doi: 10.1038/nature08476. doi: 10.1038/nature08476
[6]	Woo SR, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors[J]. Immunity, 2014, 41(5):830-842. doi: 10.1016/j.immuni.2014.10.017. doi: 10.1016/j.immuni.2014.10.017
[7]	Chan CK, Aimagambetova G, Ukybassova T, et al. Human Papillomavirus Infection and Cervical Cancer: Epidemiology, Screening, and Vaccination-Review of Current Perspectives[J]. J Oncol, 2019, 2019:3257939. doi: 10.1155/2019/3257939. doi: 10.1155/2019/3257939
[8]	Pal A, Kundu R. Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy[J]. Front Microbiol, 2019, 10:3116. doi: 10.3389/fmicb.2019.03116. doi: 10.3389/fmicb.2019.03116 pmid: 32038557
[9]	Baird JR, Feng Z, Xiao HD, et al. STING expression and response to treatment with STING ligands in premalignant and malignant disease[J]. PLoS One, 2017, 12(11):e0187532. doi: 10.1371/journal.pone.0187532. doi: 10.1371/journal.pone.0187532
[10]	Kol A, Lubbers JM, Terwindt A, et al. Combined STING levels and CD103+ T cell infiltration have significant prognostic implications for patients with cervical cancer[J]. Oncoimmunology, 2021, 10(1):1936391. doi: 10.1080/2162402X.2021.1936391. doi: 10.1080/2162402X.2021.1936391
[11]	Zhou C, Tuong ZK, Frazer IH. Papillomavirus Immune Evasion Strategies Target the Infected Cell and the Local Immune System[J]. Front Oncol, 2019, 9:682. doi: 10.3389/fonc.2019.00682. doi: 10.3389/fonc.2019.00682 pmid: 31428574
[12]	Lo Cigno I, Calati F, Albertini S, et al. Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins[J]. Pathogens, 2020, 9(4):292. doi: 10.3390/pathogens9040292. doi: 10.3390/pathogens9040292
[13]	Lau L, Gray EE, Brunette RL, et al. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway[J]. Science, 2015, 350(6260):568-571. doi: 10.1126/science.aab3291. doi: 10.1126/science.aab3291 pmid: 26405230
[14]	Shaikh MH, Bortnik V, McMillan NA, et al. cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells[J]. Microb Pathog, 2019, 132:162-165. doi: 10.1016/j.micpath.2019.05.004. doi: 10.1016/j.micpath.2019.05.004
[15]	Bortnik V, Wu M, Julcher B, et al. Loss of HPV type 16 E7 restores cGAS-STING responses in human papilloma virus-positive oropharyngeal squamous cell carcinomas cells[J]. J Microbiol Immunol Infect, 2021, 54(4):733-739. doi: 10.1016/j.jmii.2020.07.010. doi: 10.1016/j.jmii.2020.07.010
[16]	Prabakaran T, Bodda C, Krapp C, et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1[J]. EMBO J, 2018, 37(8):e97858. doi: 10.15252/embj.201797858. doi: 10.15252/embj.201797858
[17]	Luo X, Donnelly CR, Gong W, et al. HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING[J]. J Clin Invest, 2020, 130(4):1635-1652. doi: 10.1172/JCI129497. doi: 10.1172/JCI129497 pmid: 31874109
[18]	Tan YS, Sansanaphongpricha K, Xie Y, et al. Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine[J]. Clin Cancer Res, 2018, 24(17):4242-4255. doi: 10.1158/1078-0432.CCR-17-2807. doi: 10.1158/1078-0432.CCR-17-2807 pmid: 29769207
[19]	Wuebben EL, Rizzino A. The dark side of SOX2: cancer-a comprehensive overview[J]. Oncotarget, 2017, 8(27):44917-44943. doi: 10.18632/oncotarget.16570. doi: 10.18632/oncotarget.16570 pmid: 28388544
[20]	Konno H, Yamauchi S, Berglund A, et al. Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production[J]. Oncogene, 2018, 37(15):2037-2051. doi: 10.1038/s41388-017-0120-0. doi: 10.1038/s41388-017-0120-0 pmid: 29367762
[21]	Lo Cigno I, Calati F, Borgogna C, et al. Human Papillomavirus E7 Oncoprotein Subverts Host Innate Immunity via SUV39H1-Mediated Epigenetic Silencing of Immune Sensor Genes[J]. J Virol, 2020, 94(4):e01812-e01819. doi: 10.1128/JVI.01812-19. doi: 10.1128/JVI.01812-19
[22]	Lu S, Concha-Benavente F, Shayan G, et al. STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer[J]. Oral Oncol, 2018, 78:186-193. doi: 10.1016/j.oraloncology.2018.01.019. doi: 10.1016/j.oraloncology.2018.01.019
[23]	Zhu Y, An X, Zhang X, et al. STING: a master regulator in the cancer-immunity cycle[J]. Mol Cancer, 2019, 18(1):152. doi: 10.1186/s12943-019-1087-y. doi: 10.1186/s12943-019-1087-y pmid: 31679519
[24]	Dahal LN, Dou L, Hussain K, et al. STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy[J]. Cancer Res, 2017, 77(13):3619-3631. doi: 10.1158/0008-5472.CAN-16-2784. doi: 10.1158/0008-5472.CAN-16-2784 pmid: 28512240
[25]	Blitzer GC, Smith MA, Harris SL, et al. Review of the clinical and biologic aspects of human papillomavirus-positive squamous cell carcinomas of the head and neck[J]. Int J Radiat Oncol Biol Phys, 2014, 88(4):761-770. doi: 10.1016/j.ijrobp.2013.08.029. doi: 10.1016/j.ijrobp.2013.08.029
[26]	Oguejiofor K, Hall J, Slater C, et al. Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma[J]. Br J Cancer, 2015, 113(6):886-893. doi: 10.1038/bjc.2015.277. doi: 10.1038/bjc.2015.277
[27]	Cohen E, Soulières D, Le Tourneau C, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study[J]. Lancet, 2019, 393(10167):156-167. doi: 10.1016/S0140-6736(18)31999-8. doi: S0140-6736(18)31999-8 pmid: 30509740
[28]	Fessas P, Lee H, Ikemizu S, et al. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab[J]. Semin Oncol, 2017, 44(2):136-140. doi: 10.1053/j.seminoncol.2017.06.002. doi: S0093-7754(17)30055-6 pmid: 28923212
[29]	Cui P, Li R, Huang Z, et al. Comparative effectiveness of pembrolizumab vs. nivolumab in patients with recurrent or advanced NSCLC[J]. Sci Rep, 2020, 10(1):13160. doi: 10.1038/s41598-020-70207-7. doi: 10.1038/s41598-020-70207-7 pmid: 32753702
[30]	Terawaki S, Chikuma S, Shibayama S, et al. IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity[J]. J Immunol, 2011, 186(5):2772-2779. doi: 10.4049/jimmunol.1003208. doi: 10.4049/jimmunol.1003208 pmid: 21263073
[31]	Motedayen Aval L, Pease JE, Sharma R, et al. Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy[J]. J Clin Med, 2020, 9(10):3323. doi: 10.3390/jcm9103323. doi: 10.3390/jcm9103323
[32]	Shi F, Su J, Wang J, et al. Activation of STING inhibits cervical cancer tumor growth through enhancing the anti-tumor immune response[J]. Mol Cell Biochem, 2021, 476(2):1015-1024. doi: 10.1007/s11010-020-03967-5. doi: 10.1007/s11010-020-03967-5 pmid: 33141310
[33]	Pelster MS, Amaria RN. Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials[J]. Ther Adv Med Oncol, 2019, 11:1758835919830826. doi: 10.1177/1758835919830826. doi: 10.1177/1758835919830826
[34]	Baird J, Dietsh G, Florio V, et al. MV-626, a potent and selective inhibitor of ENPP1 enhances STING activation and augments T-cell mediated anti-tumor activity in vivo[C/OL]. Milwaukee(WI):SITC, 2018:Posters 7. https://digitalcommons.psjhealth.org/sitc2018/7.
[35]	Pan BS, Perera SA, Piesvaux JA, et al. An orally available non-nucleotide STING agonist with antitumor activity[J]. Science, 2020, 369(6506):eaba6098. doi: 10.1126/science.aba6098. doi: 10.1126/science.aba6098
[36]	Wehbe M, Wang-Bishop L, Becker KW, et al. Nanoparticle delivery improves the pharmacokinetic properties of cyclic dinucleotide STING agonists to open a therapeutic window for intravenous administration[J]. J Control Release, 2021, 330:1118-1129. doi: 10.1016/j.jconrel.2020.11.017. doi: 10.1016/j.jconrel.2020.11.017
[37]	Lubbers JM, Koopman B, de Klerk-Sluis JM, et al. Association of homozygous variants of STING1 with outcome in human cervical cancer[J]. Cancer Sci, 2021, 112(1):61-71. doi: 10.1111/cas.14680. doi: 10.1111/cas.14680