Isotype-switched antibodies originating from tertiary lymphoid structures can antagonize ovarian cancer progression

Many epithelial cancers orchestrate prognostically significant intratumoral tertiary lymphoid structures (TLSs), yet the mechanisms behind their antitumor activity remain unclear. Here we show that intratumoral TLS in ∼14% of human high-grade serous ovarian cancer (HGSOC) harbor highly oligoclonal B cells expressing IgA or IgG, which are not found in distant tumor regions. By engineering a recombinant antibody with the dominant B cell receptor (BCR) sequence from a mature ovarian cancer TLS, we inhibited the growth of the corresponding autologous tumor in vivo by targeting the extracellular domain of tumor-promoting GPR85. Additionally, tumor regions surrounding TLS exhibited an inflammatory environment that restricts tumor growth. TLS therefore exert anti-tumor immune pressure through the local production of isotype-switched anti-tumor antibodies and by promoting antitumor inflammation. Our results provide mechanistic insight into the elusive nature of antitumor immunity associated with TLS and underscore the importance of coordinated cellular and humoral responses in human cancer.