Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Translational Research Program, Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Sci Transl Med. 2023 Jan 11;15(678):eadd8469. doi: 10.1126/scitranslmed.add8469.
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.
小细胞肺癌（SCLC）会引发自身抗体的产生，导致独特的副肿瘤神经系统综合征。形成此类自身抗体的机制基础在很大程度上尚不清楚，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到与天然抗原结合的自身抗体。在这里，我们使用该平台筛选了 1009 个人类血浆样本中的 3600 个自身抗体-抗原复合物，发现与其他癌症患者的血浆相比，SCLC 患者的血浆平均具有四倍更高的疾病特异性自身抗体信号。在三个独立的 SCLC 队列中，我们确定了一组常见但以前未知的自身抗体，这些自身抗体是针对细胞内和细胞外肿瘤抗原产生的。我们进一步描述了这些自身抗体所针对的几种细胞外蛋白的几种疾病特异性翻译后修饰，包括瓜氨酸化、异天冬氨酸化和癌症特异性糖基化。由于大多数 SCLC 患者在诊断时就已经发生了转移性疾病，因此我们询问这些自身抗体是否可用于 SCLC 的早期检测。我们使用三个队列中的五个自身抗体创建了一个风险预测模型，平均曲线下面积为 0.84，通过将吸烟量（以包年计算）纳入其中，该模型的曲线下面积提高到了 0.96。总之，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，并深入了解疾病特异性免疫原性和临床实用性。
