Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer
Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer
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DOI：
10.1007/s00262-010-0870-9
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发表时间：
2010-09-01
影响因子：
5.8
通讯作者：
Giese, N. A.
中科院分区：
文献类型：
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作者：
Heller, A.;Zoernig, I.;Giese, N. A.
尽管存在自发或疫苗诱导的免疫应答，但胰腺癌仍然是最致命的免疫治疗抗性恶性肿瘤之一。我们试图了解胰腺肿瘤相关抗原（pTAAs）的谱，并评估其免疫原性的临床相关性。从属于长期存活者（36个月）的胰腺T3 N 0 M0/GIII标本构建的cDNA文库的自体SEREX筛选显示18个免疫原性pTAA。RT-PCR分析显示，所鉴定的抗原在正常人体组织中广泛分布。PNLIPRP 2和MIA表现出最明显的胰腺癌特异性模式。ELISA为基础的筛选血清中相应的自身抗体显示，虽然显着增加，这些分子的免疫原性不是一个共同的特点，在胰腺癌。QRT-PCR和免疫组化将PNLIPRP 2表征为稳健的腺泡细胞特异性标志物，其表达降低反映了患病器官中实质的消失，但与PNLIPRP 2自身抗体的存在无关。MIA已知优先在恶性细胞中表达，对MIA的分析令人惊讶地揭示了肿瘤内基因表达与自身抗体出现之间的负相关性。与自身抗体阳性MIA（低）患者相比，MIA（高）患者为自身抗体阴性，中位生存期较短（12 vs 34个月）。所观察到的pTAA谱包括与腺泡、基质和恶性结构相关的分子，因此为肿瘤细胞特异性治疗以及基于旁观者效应的方法提供了新的靶点。应用癌症免疫编辑的概念来解释基因表达、抗肿瘤免疫应答和临床结果之间的关系，可能会更好地区分过去和正在进行的免疫应答，从而实现患者的预后分层和免疫治疗的个体调整。
Despite spontaneous or vaccination-induced immune responses, pancreatic cancer remains one of the most deadly immunotherapy-resistant malignancies. We sought to comprehend the spectrum of pancreatic tumor-associated antigens (pTAAs) and to assess the clinical relevance of their immunogenicity. An autologous SEREX-based screening of a cDNA library constructed from a pancreatic T3N0M0/GIII specimen belonging to a long-term survivor (36 months) revealed 18 immunogenic pTAA. RT-PCR analysis displayed broad distribution of the identified antigens among normal human tissues. PNLIPRP2 and MIA demonstrated the most distinct pancreatic cancer-specific patterns. ELISA-based screening of sera for corresponding autoantibodies revealed that although significantly increased, the immunogenicity of these molecules was not a common feature in pancreatic cancer. QRT-PCR and immunohistochemistry characterized PNLIPRP2 as a robust acinar cell-specific marker whose decreased expression mirrored the disappearance of parenchyma in the diseased organ, but was not related to the presence of PNLIPRP2 autoantibodies. Analyses of MIA-known to be preferentially expressed in malignant cells-surprisingly revealed an inverse correlation between intratumoral gene expression and the emergence of autoantibodies. MIA(high) patients were autoantibody-negative and had shorter median survival when compared with autoantibody-positive MIA(low) patients (12 vs. 34 months). The observed pTAA spectrum comprised molecules associated with acinar, stromal and malignant structures, thus presenting novel targets for tumor cell-specific therapies as well as for approaches based on the bystander effects. Applying the concept of cancer immunoediting to interpret relationships between gene expression, antitumor immune responses, and clinical outcome might better discriminate between past and ongoing immune responses, consequently enabling prognostic stratification of patients and individual adjustment of immunotherapy.