Tumor-draining lymph nodes in ovarian cancer lack germinal centers but harbor tumor-reactive memory B cells clonally linked to intra-tumoral B cells

The presence of B cells in tumors is correlated with a positive prognosis in several types of cancers, including high-grade serous ovarian cancer (HGSOC). These cells give rise to plasma cells (PCs) that originate from germinal centers (GCs) and secrete tumor-reactive antibodies. GCs also give rise to memory B cells (MBCs); yet, it is unknown if tumor-reactive MBCs form in cancer patients. Single-cell RNA-seq revealed that retroperitoneal lymph nodes (LNs) located near the tumor, host primarily class-switched resting MBCs. Immunoglobulin sequencing, clonal analysis, and generation of monoclonal antibodies demonstrated that these MBCs carried tumor-reactive antibodies, some of which bind MMP14, an enzyme abundantly expressed by HGSOC tumors. Although tumor-associated retroperitoneal LNs did not exhibit an active immune response, tumor binding of the MBCs derived from these LNs was dependent on somatic hypermutations (SHM), suggesting that they originated from a previous GC reaction. Different and overlapping types of MBC subpopulations were detected in the primary tumor and associated patient-matched LNs, some of which show clonal relationships between the two sites. Thus, our study extends our understanding of the anti-tumor memory response by revealing an inter-organ link between tumor-reactive MBC clones in ovarian cancer patients, which could potentially be manipulated in ovarian cancer patients.