Abstract 6036: Mining tumor B cell repertoires for the identification of novel antibody target pairs

Abstract Tumor-infiltrating B cells and especially B cells organized in tertiary lymphoid structures (TLS) correlate with better prognosis in lung, ovarian and colon cancer patients. TLS are ectopic lymphoid organs which may present B cell follicles of germinal center. B cells in the TLS were found to express typical markers of late-stage maturation, somatic hypermutation and class switch recombination of immunoglobulin genes, indicating a cancer-driven clonal expansion. In some cases, research showed that secreted immunoglobulins of the repertoire were having a direct tumor killing activity. To decipher and then harness the potential of these tumor-trained antibodies, we analyze recombinant cognate repertoires of tumor infiltrating B cells from lung, ovarian and colon cancer surgical resections. We leverage the capabilities of our cutting-edge single-cell microfluidic platform, to extract and clone the comprehensive B cell antibody arsenal from up to a million tumor-derived B cells. The cancer derived antibodies are then expressed as recombinant full-length human IgG maintaining the heavy and light chain pairing of the original B cells. The antibody repertoire obtained as a recombinantly expressed mixture or as individual monoclonals is then screened in a panel of assays designed to identify antibodies with a function of interest. For instance, identification of antibodies showing specific binding to cancer cells. Once identified, the monoclonal antibody is then used to deconvolute novel tumor associated antigens. An initial assessment of the tumor derived antibody repertoire revealed that a typical sample of approximately one cubic centimeter of tumor tissue yielded thousands of antibody-clonotypes. The sequences pattern bore signs of affinity maturation and clonal expansion which may indicate an antigen-driven evolutionary pressure exercised by the tumor and tumor surroundings. Screening the tumor derived antibody repertoire for binding to cancer cell lines, we identified several monoclonal antibodies specifically binding to cancer cells. In vitro, these antibodies show anti-tumor activity with several mechanisms of actions: direct growth inhibition or via effector functions (antibody-dependent cell-mediated cytotoxicity). Some antibodies are strongly internalized and meditate killing when coupled to a toxic payload. The tumor antigens of the antibodies are currently being evaluated as potential therapeutic targets. These promising results may lead us to discover novel tumor pathways and contribute to our further understanding of B cell biology in cancer. Citation Format: Matthieu Delince, Carlo Zimarino, Julia Steiger, Pattraporn Satitsuksanoa, Justina Rutkauskaite, Eveline Keller, Leandra Zehnder, Lorenza Ferretti, Simone Schmitt, Christoph Esslinger. Mining tumor B cell repertoires for the identification of novel antibody target pairs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6036.