Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer

自身抗体 医学 免疫原性 抗原 免疫学 癌症 疾病 癌症研究 抗体 内科学
作者
Kristin J. Lastwika,Andrew G. Kunihiro,Joell L. Solan,Yuzheng Zhang,Lydia R. Taverne,David Shelley,Jung-hyun Rho,Timothy W. Randolph,Christopher I. Li,Eric L. Grogan,Pierre P. Massion,Annette L. Fitzpatrick,David MacPherson,A. McGarry Houghton,Paul D. Lampe
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:15 (678) 被引量:9
标识
DOI:10.1126/scitranslmed.add8469
摘要

Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.
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