2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.13: Auto-antibodies identify neoepitopes of carbonic anhydrase-9 in SCLC

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The study by Armstrong et al., conducted at Fred Hutch Cancer Center, explores the presence and implications of pathogenic autoantibodies (AAbs) in small cell lung cancer (SCLC). This type of cancer is linked with the production of AAbs that lead to paraneoplastic neurological syndromes. The researchers validate 22 AAb-antigen complexes not associated with these syndromes and report a significantly lower immune cell infiltration in SCLC compared to non-small cell lung cancer (NSCLC), suggesting different immune environment dynamics between these cancer types.<br /><br />Using single-cell RNA sequencing data, the study finds that SCLC tumors are sparsely infiltrated by B cells and plasma cells, significantly less than NSCLC tumors. This scarcity in immune cells might explain the ineffectiveness of immune checkpoint inhibitors in SCLC. Intriguingly, B cells within SCLC tumors express various immunoglobulin isotypes, indicating that these B cells are antigen-experienced. The study further examines specific AAb targets, focusing on carbonic anhydrase-9 (CA-9), a protein expressed in different SCLC subtypes and identified as a potential therapeutic target due to its stable expression throughout disease progression.<br /><br />The researchers identify 34 posttranslational modification (PTM) sites on CA9 that elicit AAb production, with 8 PTMs binding more AAbs from SCLC samples compared to controls. Two PTMs were particularly recognized by AAbs in SCLC and also in pancreatic neuroendocrine tumors, which express CA9 similarly, indicating a common feature that could be therapeutically targeted. The findings highlight how SCLC activates B cells and targets protein-level neoantigens, suggesting novel avenues for developing SCLC therapies.

Asset Subtitle

Dominique Armstrong

Keywords

small cell lung cancer

pathogenic autoantibodies

paraneoplastic neurological syndromes

immune cell infiltration

single-cell RNA sequencing

immune checkpoint inhibitors

carbonic anhydrase-9

posttranslational modifications

B cells

therapeutic targets