IgA transcytosis and antigen recognition govern ovarian cancer immunity

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.

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Policy information about availability of computer code Data collection FACS data was collected from BD FACS LSR II and BD FACS ARIA using BD FACS Diva v8.0.1. Multiplex data was collected from PerkinElmer Vectra®3 Automated Quantitative Pathology Imaging System inForm v2.4.8. RNA Sequencing reads were collected using bcl2fastq v2.20. Confocal microscopy image acquisition was performed and data collected from Leica SP8 using LAS X (v3.5.5.19976). For quantitative analysis, fluorescence image acquisition was performed in Zeiss Imager Z2 upright microscope and data was collected using ZEN 2.3 (blue edition) software. H/E histology slides were scanned in Aperio-Leica Scanner Console (v102.0.7.5) and data were collected.
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April 2020
Data Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability The RNA sequencing data and single cell BCR sequencing data related to this study are available at the NCBI Gene Expression Omnibus (GEO) under accession number GSE146820. The mass spectrometry proteomics data are available in PRIDE with identifier PXD018079. Source data are provided with this paper. Molecular and clinical data from The Cancer Genome Atlas for Ovarian Serous Cystadenocarcinoma (OV) are available at the cBio Cancer Genomics Portal (http:// www.cbioportal.org/), Broad Firehose website (https://gdac.broadinstitute.org/), and Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/). Source data are provided with this paper. The datasets generated during the current study are available from the corresponding author upon reasonable request.

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