PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer, with minimal response to therapeutic intervention and with 85% of cases diagnosed at an advanced stage due to lack of early symptoms, highlighting the importance of understanding PDAC immunology in greater detail. Here, we applied an immunoproteomic approach to investigate autoantibody responses against cancer-testis and tumor-associated antigens in PDAC using a high-throughput multiplexed protein microarray platform, comparing humoral immune responses in serum and at the site of disease in order to shed new light on immune responses in the tumor microenvironment. We simultaneously quantified serum or tissue IgG and IgA antibody isotypes and subclasses in a cohort of PDAC, disease control and healthy patients, observing inter alia that subclass utilization in tumor tissue samples was predominantly immune suppressive IgG4 and inflammatory IgA2, contrasting with predominant IgG3 and IgA1 subclass utilization in matched sera and implying local autoantibody production at the site of disease in an immune-tolerant environment. By comparison, serum autoantibody subclass profiling for the disease controls identified IgG4, IgG1, and IgA1 as the abundant subclasses. Combinatorial analysis of serum autoantibody responses identified panels of candidate biomarkers. The top IgG panel included ACVR2B, GAGE1, LEMD1, MAGEB1 and PAGE1 (sensitivity, specificity and AUC values of 0.933, 0.767 and 0.906). Conversely, the top IgA panel included AURKA, GAGE1, MAGEA10, PLEKHA5 and XAGE3aV1 (sensitivity, specificity, and AUC values of 1.000, 0.800, and 0.954). Assessment of antigen-specific serum autoantibody glycoforms revealed abundant sialylation on IgA in PDAC, consistent with an immune suppressive IgA response to disease.
摘要：
胰腺导管腺癌（PDAC）是一种异质性癌症，对治疗干预反应最小，85%的病例因缺乏早期症状而诊断为晚期，强调更详细地理解PDAC免疫学的重要性。这里,我们应用免疫蛋白质组学方法，使用高通量多重蛋白质微阵列平台，研究PDAC中针对癌症睾丸和肿瘤相关抗原的自身抗体反应。比较血清和疾病部位的体液免疫反应，以揭示肿瘤微环境中的免疫反应。我们在一组PDAC中同时定量血清或组织IgG和IgA抗体同种型和亚类，疾病控制和健康患者，观察到肿瘤组织样本中的亚类利用主要是免疫抑制性IgG4和炎性IgA2,与匹配血清中的主要IgG3和IgA1亚类利用形成对比,并暗示在免疫耐受环境中在疾病部位产生局部自身抗体.相比之下,疾病对照的血清自身抗体亚类分析确定IgG4,IgG1和IgA1为丰富亚类.血清自身抗体应答的组合分析鉴定了候选生物标志物组。顶部IgG面板包括ACVR2B，GAGE1,LEMD1,MAGEB1和PAGE1(灵敏度,特异性和AUC值分别为0.933、0.767和0.906)。相反，顶级IgA面板包括AURKA，GAGE1,MAGEA10,PLEKHA5和XAGE3aV1(灵敏度,特异性，和AUC值为1.000、0.800和0.954)。对抗原特异性血清自身抗体糖型的评估显示PDAC中IgA的唾液酸化丰富，与免疫抑制IgA对疾病的反应一致。
