HPV6/11持续感染与复发性呼吸道乳头状瘤病治疗相关免疫重塑：一项跨队列转录组分析

文献信息

中文摘要

背景： 复发性呼吸道乳头状瘤病（RRP）主要由人乳头瘤病毒6型和11型（HPV6/11）引起，尽管未发现明确的系统性免疫缺陷，该病仍可持续存在。方法：我们使用相同的预设免疫基因程序重新分析了三个转录组数据集：12例患者的配对乳头状瘤与自体喉黏膜、4例RRP供者乳头状瘤与3例对照的腭咽黏膜的单细胞RNA测序，以及17例患者接受INO-3107（一种编码HPV6/11抗原和白细胞介素12的DNA免疫疗法）前后的配对乳头状瘤样本。结果：在未治疗组织中，分化簇8（CD8）和自然杀伤（NK）相关细胞毒性程序评分较低，转化生长因子β（TGF-β）抑制性程序评分较高，重现了同一队列的发现。在回收的合并T细胞和NK细胞群体中，未重现较低的细胞毒性模式，尽管经多重检验校正后没有任何单细胞比较仍具有显著性。接受INO-3107后，CD8和NK相关细胞毒性、T辅助1型（Th1）/干扰素γ（IFN-γ）以及C-X-C基序趋化因子受体3（CXCR3）相关运输程序评分显著升高，而TGF-β和M2样抑制性程序未显示具有统计学支持的相应变化。结论：总之，这些发现表明局部免疫反应的不同组分并非平行变化，并支持选择性治疗相关免疫重塑的模型。这一模式可能为未来的生物标志物和联合治疗研究提供信息。

英文摘要

Recurrent respiratory papillomatosis (RRP), caused mainly by human papillomavirus types 6 and 11 (HPV6/11), can persist despite the absence of recognized systemic immunodeficiency. We reanalyzed three transcriptomic datasets using the same predefined immune-gene programs: paired papilloma and autologous laryngeal mucosa from 12 patients, single-cell RNA sequencing from papillomas of four RRP donors and pharyngopalatine mucosa from three controls, and paired papilloma samples from 17 patients before and after INO-3107, a DNA immunotherapy encoding HPV6/11 antigens and interleukin-12. In untreated tissue, cluster of differentiation 8 (CD8)- and natural killer (NK)-associated cytotoxic program scores were lower and the transforming growth factor beta (TGF-β) suppressive program score was higher, reproducing findings from the same cohort. The lower cytotoxic pattern was not reproduced within the recovered combined T-cell and NK-cell population, although no single-cell comparison remained significant after correction for multiple testing. After INO-3107, CD8- and NK-associated cytotoxic, T helper 1 (Th1)/interferon gamma (IFN-γ), and C-X-C motif chemokine receptor 3 (CXCR3)-associated trafficking program scores increased significantly, whereas TGF-β and M2-like suppressive programs showed no comparable statistically supported change. Together, these findings show that different components of the local immune response do not change in parallel and support a model of selective treatment-associated immune remodeling. This pattern may inform future biomarker and combination-treatment studies.