IgA transcytosis and antigen recognition govern ovarian cancer immunity

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.

Immunoglobulin Expression in Cancer Cells and Its Critical Roles in Tumorigenesis

“…Ig is a well-known molecule essential for the humoral immune response, but its roles in tumorigenesis are far from clear. Some studies have elucidated the effects of Ig on B cell infiltration in the tumor microenvironment, but many phenomena are still difficult to understand from the perspective of B cell-derived Ig (105)(106)(107). The identification of cancer-derived Ig is undoubtedly a significant finding in the current research area of Ig and largely improves the understanding of Ig in tumorigenesis.…”

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

“…In prostate cancer and hepatocellular carcinoma, IgAproducing plasma cells have been shown to function as potent immunosuppressive cell populations through the expression of IL-10 and PD-L1 (Shalapour et al, 2015(Shalapour et al, , 2017. On the other hand, in ovarian cancer, a recent report demonstrated that protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors universally expressed on the tumor cells (Biswas et al, 2021). Interestingly, IgA responses were shown to impair ovarian cancer growth through complementary mechanisms: antigen-specific IgA redirected myeloid cells against cell-surface antigen-positive tumor cells, while transcytosis of non-antigen-specific IgA by tumor cells induced broad transcriptional changes, including the upregulation of IFN-γ receptors and several DUSP phosphatases, which antagonize the RAS pathway.…”

Fantastic IgA plasma cells and where to find them

“…The immune system plays a complex role in the tumor microenvironment. In some instances, the immune system has been implicated in promoting the growth and metastatic capacity of malignant cells, while in other instances, the innate and adaptive immune branches have eradicated malignant cells thereby preventing tumor growth 154‐161 . This duality has been explored in studies specifically investigating the heterogeneity of B cells and PC in human malignancies over the last few years, with more recent data exploring IgA + PC in cancer.…”