The ABCs of ovarian cancer immunology: IgA, B cells, and CTLs

See allHide authors and affiliations

Science Immunology  05 Mar 2021:
Vol. 6, Issue 57, eabh3184
DOI: 10.1126/sciimmunol.abh3184


Intratumoral B cells in ovarian cancers produce IgA, which binds tumor antigens and inhibit tumor growth through myeloid cell–dependent mechanisms or by neutralization of secreted factors, and by antigen-nonspecific binding to poly-Ig receptor on cancer cells leading to transcytosis, which sensitizes the cells for CTL killing.

Previous studies have shown correlations of both T and B cell/plasma cell infiltrates in ovarian carcinomas with improved prognosis, but how these responses affect tumor growth are unknown, and immune checkpoint inhibitors have so far shown little efficacy in ovarian cancer. Biswas et al. sought to better understand the B cell responses to ovarian cancer by studying tumors from 534 patients with high-grade serous ovarian cancer (HGSOC). They first confirmed that intratumoral B cell infiltrates associated with better survival, as did T cells, but only when they co-infiltrated with B cells. Surprisingly, they found that the dominant isotype expressed by intratumoral B cells was IgA, and the IgA was bound to HGSOC cells in the tumor. They also found that HGSOC cells uniformly express the poly-Ig receptor (PIGR), which coimmunoprecipitates with IgA. Confocal microscopic studies showed that IgA, but not pepsin-treated IgA lacking Fc, translocated through ovarian carcinoma cells, but not through cancer cells with CRISPR-mediated PIGR-gene ablation. Transcriptional and protein analyses indicated that IgA transcytosis induced many changes in gene expression in tumor cells, such as increased IFNγ receptor, down-regulation of ephrins, and increases in phosphatases that impair RAS/MEK/ERK signaling. The investigators next showed that IgA sensitized tumor cells to CTL-mediated killing in vitro and in vivo in an Fc/PIGR-dependent manner. These IgA effects were seen with antigen-nonspecific polyclonal IgA. The authors determined the specificities of IgAs produced by some intratumoral B cells and showed that the anti-tumor activity of these IgAs in mice depended on PIGR-expressing myeloid cells and antibody-mediated phagocytosis of the antigen bearing tumor cells. For IgAs specific for the secreted tumor-enhancing protein BDNF, anti-tumor activity was retained after pepsin treatment, suggesting a neutralization mechanism. Overall, this study offers several different findings consistent with the conclusion that IgA produced by B cells within ovarian carcinomas inhibits ovarian cancer growth, by enhancing susceptibility to T cell killing via IgA-transcytosis, and by specifically binding tumor antigens. These findings suggest methods that enhance tumor B cell IgA responses, or perhaps treatments with tumor-antigen specific IgA, may synergize with methods to enhance T cell activation, for effective immunotherapy for ovarian cancer.

Highlighted Article

Stay Connected to Science Immunology

Navigate This Article