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

Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neu-rological 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 au-toantibodies 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 previ-ously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor an-tigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glyco-sylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these au-toantibodies 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 ap-proach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunoge-nicity and clinical utility.