Tumor-derived Autoantibodies Identify Malignant Pulmonary Nodules

Abstract

Rationale: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm caused by invasive follow-up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor-specific biomarkers.Objectives: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules.Methods: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule control subjects. Promising autoantibodies were further analyzed in an independent cohort of 250 nodulepositive patients.Measurements and Main Results: Thirteen tumor B-cell-derived autoantibodies isolated ex vivo showed greater than or equal to 50% sensitivity and greater than or equal to 70% specificity for lung cancer. In plasma, 11 of 13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5 of 13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of four of these autoantibodies could detect malignant nodules with an area under the curve of 0.74 and had an area under the curve of 0.78 in a subcohort of indeterminate (8-20 mm in the longest diameter) pulmonary nodules.Conclusions: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and noninvasive approach to determine nodule malignancy for widespread low-dose computed tomography screening.

The Immune Endocannabinoid System of the Tumor Microenvironment

“…Another anti-tumorigenic effect of B cells is mediated by anti-tumor antibodies, as recently reviewed by Sharonov et al [ 61 ]. Cancer-specific neo-antigens, such as mutated p53 [ 65 ], but also self-proteins represent targets for antibodies in tumors [ 66 , 67 ]. Infiltrating B cells were reported as an important predictor for good clinical outcome in patients with metastatic melanoma [ 68 ].…”

Narrative review: indeterminate pulmonary nodules

“…Antibody-based biomarkers have also been explored. Lastwika and colleagues isolated a set of autoantibodies from tumor-infiltrating B cells in NSCLC and matched them to known cancer antigens using a protein screen (51). They found that autoantibodies in NSCLC are not only found in peripheral plasma but are also specific for malignant nodules.…”

Liquid biopsies to distinguish malignant from benign pulmonary nodules

“…70 In a recent study, Lastwika et al defined 11 AAb isolated from B cells of 10 resected lung tumors by high-density protein arrays, and demonstrated that a combination of four AAb (FCGR2A, EPB41L3, LINGO1 and S100A7L2) could detect indeterminate (8-20 mm) pulmonary nodules with a sensitivity and specificity of 91.7 and 57.1%. 71…”