Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer.
Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer.
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DOI：
10.1126/scitranslmed.add8469
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发表时间：
2023-01-11
影响因子：
17.1
通讯作者：
Lampe, Paul D.
中科院分区：
文献类型：
--
作者：
Lastwika, Kristin J.;Kunihiro, Andrew;Solan, Joell L.;Zhang, Yuzheng;Taverne, Lydia R.;Shelley, David;Rho, Jung-Hyun;Randolph, Timothy W.;Li, Christopher I.;Grogan, Eric L.;Massion, Pierre P.;Fitzpatrick, Annette L.;MacPherson, David;Houghton, A. McGarry;Lampe, Paul D.
小细胞肺癌（SCLC）导致自身抗体的产生，导致独特的副肿瘤性神经综合征。这种自身抗体形成的机制基础在很大程度上是未知的，但这是理解其病因的关键。我们开发了一种高维技术，能够直接从患者血浆中检测与天然抗原复合的自身抗体。在这里，我们使用我们的平台筛选了1，009份人类血浆样本中的3，600种自身抗体-抗原复合物，发现SCLC患者的血浆平均含有比其他癌症患者血浆高4倍的疾病特异性自身抗体信号。在3个独立的SCLC队列中，我们鉴定了一组常见但以前未知的自身抗体，其响应于细胞内和细胞外肿瘤抗原而产生。我们进一步表征了这些自身抗体靶向的细胞外蛋白内的几种疾病特异性翻译后修饰，包括瓜氨酸、异戊酰化和癌症特异性糖基化。由于大多数SCLC患者在诊断时有转移性疾病，我们询问这些自身抗体是否可用于SCLC早期检测。我们使用5种自身抗体创建了一个风险预测模型，其中3个队列的平均曲线下面积为0.84，通过将香烟烟雾消费量纳入包年，该曲线下面积提高到0.96。综上所述，我们的研究结果提供了一种创新的方法来识别SCLC中的循环自身抗体，并对疾病特异性免疫原性和临床实用性进行了深入研究。小细胞肺癌产生可用于肿瘤早期检测的自身抗体靶向的肿瘤相关抗原。
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 1,009 human plasma samples for 3,600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, 4-fold higher disease-specific autoantibody signals compared to plasma from patients with other cancers. Across 3 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 post translational modifications within extracellular proteins targeted by these autoantibodies including citrullination, isoaspartylation and cancer-specific glycosylation. Since most patients with SCLC have metastatic disease at diagnosis, we queried if these autoantibodies could be utilized for SCLC early detection. We created a risk-prediction model using 5 autoantibodies with an average area under the curve of 0.84 for the 3 cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Taken together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility. Small cell lung cancer generates tumor associated antigens targeted by autoantibodies that can be exploited for tumor early detection.
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DOI：
10.1016/j.jtho.2017.09.1951
发表时间：
2018-01
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Almodovar K;Iams WT;Meador CB;Zhao Z;York S;Horn L;Yan Y;Hernandez J;Chen H;Shyr Y;Lim LP;Raymond CK;Lovly CM
通讯作者：
Lovly CM
影响因子：
9.9
作者：
Gozzard, Paul;Woodhall, Mark;Maddison, Paul
通讯作者：
Maddison, Paul
影响因子：
3.7
作者：
Gozzard, Paul;Chapman, Caroline;Maddison, Paul
通讯作者：
Maddison, Paul
影响因子：
7
作者：
Doyle HA;Mamula MJ
通讯作者：
Mamula MJ
影响因子：
11.1
作者：
Fernandez-Cuesta L;Perdomo S;Avogbe PH;Leblay N;Delhomme TM;Gaborieau V;Abedi-Ardekani B;Chanudet E;Olivier M;Zaridze D;Mukeria A;Vilensky M;Holcatova I;Polesel J;Simonato L;Canova C;Lagiou P;Brambilla C;Brambilla E;Byrnes G;Scelo G;Le Calvez-Kelm F;Foll M;McKay JD;Brennan P
通讯作者：
Brennan P