Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy.
Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy.
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DOI：
10.1177/2051013617717914
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发表时间：
2017-06-01
期刊：
影响因子：
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通讯作者：
Stern, Peter L
中科院分区：
文献类型：
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作者：
Smola, Sigrun;Trimble, Connie;Stern, Peter L
现在人们认识到，免疫系统可以是肿瘤过程中约束和控制的关键组成部分。人类乳头瘤病毒(HPV)相关的肛门生殖道和口咽癌是一个重要的临床问题，但有一个明显的机会免疫靶向的病毒癌基因表达，推动癌症的发展。然而，靶上皮细胞的高危HPV感染和E6/E7癌基因的表达可导致先天免疫系统的早期损害(抗原提呈细胞的丧失)，促进病毒的持续存在和癌症风险的增加。在这些情况下，通过调节不同的免疫受体、趋化因子和细胞因子反应(CCL20；CCL2；CCR2；IL-6；CCR7；IL-12)，一系列相互作用和自我增强的事件进一步促进免疫抑制微环境的产生[Tregs，Th17，髓系衍生抑制细胞(MDSCs)和PD-L1水平增加]。E6/E7的过度表达还损害了修复细胞DNA的能力，导致基因组不稳定，获得的基因变化为选择优势癌细胞提供了包括免疫逃逸的额外策略。针对HPV癌基因的治疗性疫苗在最近的一些早期临床试验中显示出一些令人鼓舞的成功，这些试验在HPV相关的高级别肛门生殖器病变患者中进行了测试。在更严重的疾病中取得成功的一个重要障碍将是局部和全身免疫抑制因素。针对不同免疫抑制成分的干预可以提供释放现有的或产生新的有效的抗肿瘤免疫的机会。改变前列腺癌炎症环境的治疗包括Toll样受体刺激、抑制IL-6相关通路、免疫检查点抑制、直接调节MDSCs、Tregs和巨噬细胞，这些都可能与治疗性HPV疫苗相结合。未来在提供成功的免疫疗法方面的进展将取决于有洞察力的及时组合的治疗方案的配置。
It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.