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.
Highlights
To characterize the role of B cells in ovarian cancer, we first stained a panel of 534 annotated high-grade serous ovarian cancers (HGSOCs) from 3 independent cohorts with T and B cell markers
Intracellular staining of plasma cells and CD19+CD20−CD38highCD27+ cells revealed the dominant production of class-switched IgA, followed by IgG; this is consistent with mRNA expression data from The Cancer Genome Atlas (TCGA) (Fig. 1a, Extended Data Figs. 1g–i, 2a, b) and with surface staining of B cells (Fig. 1a, Extended Data Fig. 1g–i)
As previously reported[6], CD138+ plasma cell infiltrates were associated with improved survival in patients with HGSOC (Extended Data Fig. 2c), were identified in 80% of dissociated tumours in >1% of total leukocytes and correlated with intratumoural T cells (Extended Data Fig. 2d, e)
Summary
Subir Biswas[1], Gunjan Mandal[1], Kyle K. Recent studies have suggested that plasma cell and memory B cell infiltrates, including those in tertiary lymphoid structures[8], are associated with the cytolytic activity of T cells at ovarian cancer beds, resulting in improved survival of patients[5,6]. These studies suggest that humoral responses may potentiate T cell immune surveillance, the roles of different antibody isotypes in malignant progression are controversial. We found universal expression of the polymeric immunoglobulin receptor (pIgR)
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