Authors: Biswas, Subir; Mandal, Gunjan; Payne, Kyle K.; Anadon, Carmen M.; Gatenbee, Chandler D.; Chaurio, Ricardo A.; Costich, Tara Lee; Moran, Carlos; Harro, Carly M.; Rigolizzo, Kristen E.; Mine, Jessica A.; Trillo-Tinoco, Jimena; Sasamoto, Naoko; Terry, Kathryn L.; Marchion, Douglas; Buras, Andrea; Wenham, Robert M.; Yu, Xiaoqing; Townsend, Mary K.; Tworoger, Shelley S.; Rodriguez, Paulo C.; Anderson, Alexander R.; Conejo-Garcia, Jose R.
Issue: Nature . 2021 Mar;591(7850):464-470.
Most ovarian cancers are infiltrated by prognostically relevant activated T cells1–3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.