Clonally related tumor-reactive memory B cells reside in primary tumors and lymph nodes of ovarian cancer patients

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)1–4. These B cells give rise to plasma cells (PCs) that originate from germinal centers (GCs) and secrete tumor-reactive antibodies5,6. GCs also give rise to memory B cells (MBCs)7,8; yet, it is not known if tumor-reactive MBCs form and disperse in cancer patients. Single-cell RNA-seq revealed that tumor-draining lymph nodes (LNs) do not support a robust B cell immune response, and primarily host quiescent class-switched MBCs. Immunoglobulin sequencing, clonal analysis, and generation of monoclonal antibodies demonstrated that these MBCs expressed tumor-reactive antibodies, some of which bound MMP14, an enzyme abundantly expressed by HGSOC tumors5. Although tumor-associated LNs did not exhibit mature GC structures, 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 MBC subpopulations were detected in the primary tumor and LNs from the same patient, some of which were clonally related between the two sites, and showed intratumoral PC-differentiation potential. Thus, our study extends our understanding of the anti-tumor memory response by revealing an inter-organ association between tumor-reactive MBC clones, which could potentially be manipulated in ovarian cancer patients.