IgA transcytosis and antigen recognition govern ovarian cancer immunity

Subir Biswas, Gunjan Mandal, Kyle K. Payne, Carmen M. Anadon, Chandler D. Gatenbee, Ricardo A. Chaurio, Tara Lee Costich, Carlos Moran, Carly M. Harro, Kristen E. Rigolizzo, Jessica A. Mine, Jimena Trillo-Tinoco, Naoko Sasamoto, Kathryn L. Terry, Douglas Marchion, Andrea Buras, Robert M. Wenham, Xiaoqing Yu, Mary K. Townsend, Shelley S. Tworoger, Paulo C. Rodriguez, Alexander R. Anderson and Jose R. Conejo-Garcia ()
Additional contact information
Subir Biswas: H. Lee Moffitt Cancer Center and Research Institute
Gunjan Mandal: H. Lee Moffitt Cancer Center and Research Institute
Kyle K. Payne: H. Lee Moffitt Cancer Center and Research Institute
Carmen M. Anadon: H. Lee Moffitt Cancer Center and Research Institute
Chandler D. Gatenbee: H. Lee Moffitt Cancer Center and Research Institute
Ricardo A. Chaurio: H. Lee Moffitt Cancer Center and Research Institute
Tara Lee Costich: H. Lee Moffitt Cancer Center and Research Institute
Carlos Moran: H. Lee Moffitt Cancer Center and Research Institute
Carly M. Harro: H. Lee Moffitt Cancer Center and Research Institute
Kristen E. Rigolizzo: H. Lee Moffitt Cancer Center and Research Institute
Jessica A. Mine: H. Lee Moffitt Cancer Center and Research Institute
Jimena Trillo-Tinoco: H. Lee Moffitt Cancer Center and Research Institute
Naoko Sasamoto: Brigham and Women’s Hospital and Harvard Medical School
Kathryn L. Terry: Brigham and Women’s Hospital and Harvard Medical School
Douglas Marchion: Brigham and Women’s Hospital and Harvard Medical School
Andrea Buras: H. Lee Moffitt Cancer Center and Research Institute
Robert M. Wenham: H. Lee Moffitt Cancer Center and Research Institute
Xiaoqing Yu: H. Lee Moffitt Cancer Center and Research Institute
Mary K. Townsend: H. Lee Moffitt Cancer Center and Research Institute
Shelley S. Tworoger: H. Lee Moffitt Cancer Center and Research Institute
Paulo C. Rodriguez: H. Lee Moffitt Cancer Center and Research Institute
Alexander R. Anderson: H. Lee Moffitt Cancer Center and Research Institute
Jose R. Conejo-Garcia: H. Lee Moffitt Cancer Center and Research Institute

Nature, 2021, vol. 591, issue 7850, 464-470

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-020-03144-0

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