Hernandez Puente Cinthia Violeta, Hsu Ping-Ching, Rogers Lora J, Jousheghany Fariba, Siegel Eric, Kadlubar Susan A, Beck J Thaddeus, Makhoul Issam, Hutchins Laura F, Kieber-Emmons Thomas, Monzavi-Karbassi Behjatolah
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
UnivLyon, Université Claude Bernard Lyon 1, Lyon, France.
Front Oncol. 2020 Jun 5;10:879. doi: 10.3389/fonc.2020.00879. eCollection 2020.
Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes, tumorigenicity and tumor progression, we aimed to analyze pre-vaccination DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) from breast cancer subjects vaccinated with a novel peptide-based vaccine referred to as P10s-PADRE. This pilot study was performed to evaluate whether signatures of differentially methylated (DM) loci can be developed as potential predictive biomarkers for prescreening subjects with cancer who will most likely generate an immune response to the vaccine. Genomic DNA was isolated from PBMCs of eight vaccinated subjects, and their DNA methylation profiles were determined using Infinium MethylationEPIC BeadChip array from Illumina. A linear regression model was applied to identify loci that were differentially methylated with respect to anti-peptide antibody titers and with IFN-γ production. The data were summarized using unsupervised-learning methods: hierarchical clustering and principal-component analysis. Pathways and networks involved were predicted by Ingenuity Pathway Analysis. We observed that the profile of DM loci separated subjects in regards to the levels of immune responses. Canonical pathways and networks related to metabolic and immunological functions were found to be involved. The data suggest that it is feasible to correlate methylation signatures in pre-treatment PBMCs with immune responses post-treatment in cancer patients going through standard-of-care chemotherapy. Larger and prospective studies that focus on DM loci in PBMCs is warranted to develop pre-screening biomarkers before BC vaccination. www.ClinicalTrials.gov, Identifier: NCT02229084.
对特定抗原的免疫反应，尤其是在癌症患者中，是复杂的，并且受多种遗传和环境因素控制。识别能够预测对免疫接种产生强烈反应的生物标志物是临床癌症疫苗开发中的迫切需求。鉴于DNA甲基化参与淋巴细胞发育、肿瘤发生和肿瘤进展，我们旨在分析接种一种名为P10s-PADRE的新型肽基疫苗的乳腺癌受试者接种前外周血单个核细胞（PBMC）的DNA甲基化谱。进行这项初步研究是为了评估差异甲基化（DM）位点的特征是否可作为潜在的预测生物标志物，用于预筛选最有可能对该疫苗产生免疫反应的癌症患者。从8名接种疫苗的受试者的PBMC中分离出基因组DNA，并使用Illumina公司的Infinium MethylationEPIC BeadChip芯片测定其DNA甲基化谱。应用线性回归模型来识别相对于抗肽抗体滴度和IFN-γ产生存在差异甲基化的位点。使用无监督学习方法（层次聚类和主成分分析）对数据进行总结。通过Ingenuity Pathway Analysis预测所涉及的通路和网络。我们观察到，DM位点的图谱根据免疫反应水平将受试者区分开来。发现与代谢和免疫功能相关的经典通路和网络参与其中。数据表明，对于接受标准护理化疗的癌症患者，将治疗前PBMC中的甲基化特征与治疗后的免疫反应相关联是可行的。有必要开展更大规模的前瞻性研究，聚焦于PBMC中的DM位点，以在乳腺癌疫苗接种前开发预筛选生物标志物。 临床试验.gov网站，标识符：NCT02229084。
