Elucidating B-cell mediated T-cell responses in esophagogastric adenocarcinoma

• Applicant: Professor Dr. Hans Anton Schlößer
• Subject Area: General and Visceral Surgery ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572682349

B cells represent an important component of the tumor microenvironment (TME) and affect naturally occurring anti-tumor immune responses as well as cancer immunotherapies. We thoroughly characterized B-cell infiltrates in the TME and detected tumor-specific antibodies to several shared antigens in different types of solid cancer. Tumor-associated B cells are usually localized in clusters in the TME. Due to similarities to lymphoid follicles in secondary lymphoid organs, these B-cell clusters have been termed tertiary lymphoid structures (TLS). Recent publications demonstrating that abundance of TLS is associated with susceptibility to immune checkpoint inhibition in melanoma and sarcoma further underline the translational relevance of B cells in solid cancers. Interestingly, TLS abundance is related to the activation of tumor-draining lymph nodes. In one of our latest publications, we described that antigen-presenting B cells localize in TLS in ten different types of cancer and that antigen-presenting B cells, which were flow-sorted from tumor-draining lymph nodes, can activate T cells, which are specific for tumor-associated antigens. We further demonstrated that antigen-presenting B cells can be used to expand tumor-specific T cells in esophageal cancer patients and that these expanded T cells show cytotoxic activity in vitro. TLS and tumor-draining lymph nodes appear as sites for antigen presentation by B cells and dendritic cells. In theory, these two different professional antigen-presenting cells may induce or enhance distinct or overlapping T-cell responses, and the related mechanisms are poorly understood. The proposed project will elucidate the major mechanisms underlying B-cell mediated T-cell responses. We will perform detailed analyses of the antigen-presenting machinery and the resulting repertoire of peptides presented on HLA-I and HLA-II molecules. We expect major differences in both aspects and hypothesize that B cells and DCs present distinct peptide repertoires, leading to distinct peptide-HLA complexes and probably complementary T-cell repertoires. The profile of expressed immune-regulatory molecules and secreted cytokines are additional major determinants of anti-tumor T-cell responses, which will be assessed by gene expression analyses and quantification of secreted cytokines. The major T-cell subsets and the T-cell receptor repertoires induced by antigen-presenting B cells will be thoroughly investigated and compared to their DC-mediated counterparts. As the project will focus on patient-derived material, we will be able to identify T-cell clones, which were preferentially expanded by B cells, in patient-matched T-cell receptor repertoires in the TME and tumor-draining lymph nodes. Finally, we will thoroughly investigate specificity and functionality of B-cell related T-cell clones. Our results will probably be of similar relevance to other types of cancer.

• DFG Programme: Research Grants