PDF(Pubmed)
Abstract：
Human papillomavirus (HPV)-associated cancer continues to evade the immune system by promoting a suppressive tumor microenvironment. Therefore, immunotherapy appears to be a promising approach for targeting HPV-associated tumors. We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the antitumor immunity in HPV-associated solid tumors. We performed bulk RNA-sequencing (RNA-Seq) on total peripheral blood mononuclear cells (PBMCs) of seven nonresponders (NRs) and four responders (Rs). A total of 39 samples (e.g., pretreatment, post-VA, postavelumab, and endpoint) were analyzed. Also, we quantified plasma analytes and performed flow cytometry. We observed a differential pattern in immune response following treatment with VA and/or avelumab in NRs vs. Rs. A significant upregulation of transcripts associated with NETosis [the formation of neutrophil extracellular traps (NETs)] and neutrophil degranulation pathways was linked to the presence of a myeloid-derived suppressor cell signature in NRs. We noted the elevation of IL-8/IL-18 cytokines and a distinct transcriptome signature at the baseline and endpoint in NRs. By using the receiver operator characteristics, we identified a cutoff value for the plasma IL-8/IL-18 to discriminate NRs from Rs. We found differential therapeutic effects for VA and avelumab in NRs vs. Rs. Thus, our results imply that measuring the plasma IL-8/IL-18 and bulk RNA-Seq of PBMCs may serve as valuable biomarkers to predict immunotherapy outcomes.
摘要：
人乳头瘤病毒（HPV）相关的癌症继续通过促进抑制性肿瘤微环境来逃避免疫系统。因此,免疫疗法似乎是靶向HPV相关肿瘤的一种有希望的方法.我们假设丙戊酸（VA）作为表观遗传因子与avelumab组合可以增强HPV相关实体瘤的抗肿瘤免疫力。我们对7个无应答者（NRs）和4个应答者（Rs）的总外周血单核细胞（PBMC）进行了大量RNA测序（RNA-seq）。共39个样本(如预处理、后VA，阿维鲁单抗后，和终点)进行分析。此外，我们定量血浆分析物并进行流式细胞术.我们观察到用VA和/或avelumab治疗后的NRs与Rs的免疫反应有差异。与NETosis[中性粒细胞胞外陷阱（NETs）的形成]和中性粒细胞脱颗粒途径相关的转录本的显着上调与NRs中髓源性抑制细胞特征的存在有关。我们注意到IL-8/IL-18细胞因子的升高和在NRs的基线和终点的不同转录组特征。通过使用接收器操作员特征，我们确定了血浆IL-8/IL-18的截断值以区分R.我们发现在NRs和Rs中VA和avelumab的治疗效果不同。因此，我们的结果表明,测量血浆IL-8/IL-18和PBMC的大量RNA-seq可能是预测免疫治疗结局的有价值的生物标志物.
