IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer

Abstract

Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies. Significance: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766

Mistic: An open-source multiplexed image t-SNE viewer

“…These insights derived from Mistic combined with detailed statistical analysis helped reinforce the findings in the study that IgA was a key player in predicting survival and that immune protection, leading to better survival, was associated with tumors with pIgR + IgA and, to a lesser extent, pIgR + IgG.

Figure 10 Mistic renders 210 tissue microarray (TMA) cores of endometrial cancer 28 arranged in rows Each core depicts pIgR on tumor cells (blue), IgA (black), IgG (pink), plasma cells (red), additional B cells (green), and unstained cells (gray). Each core has a border that matches the cluster it belongs to (see the Cluster Annotations live panel).

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“…Each core has a border that matches the cluster it belongs to (see the Cluster Annotations live panel).

Figure 11 Mistic for 210 TMA cores of endometrial cancer 28 (A) Image t-SNE rendering using Mistic for 210 TMA cores of endometrial cancer. 41 Each core depicts pIgR on tumor cells (blue), IgA (black), IgG (pink), plasma cells (red), additional B cells (green), and unstained cells (gray).

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“… The endometrial cancer images reported in this work can be made available by contacting the lead author of the study. 28 The human colorectal cancer is publicly available. 42 Section 2 : Code All original code has been deposited at Zenodo: https://doi.org/10.5281/zenodo.5912169 and is publicly available as of the date of publication.…”

“…Motivated by the usefulness of the image t-SNE in our work and in our recent analysis of endometrial cancer, 28 which we discuss in section tissue microarray cores for endometrial cancer , we have developed Mistic, an open-source multiplexed image t-SNE viewer that enables the simultaneous viewing of multiple 2D images rendered using multiple layout options to provide an overall visual preview of the entire dataset. In particular, the positions of the images can be taken from t-SNE or UMAP coordinates.…”

Crosstalk of Redox-Related Subtypes, Establishment of a Prognostic Model and Immune Responses in Endometrial Carcinoma

“…B cells also have a vital effect on anti-tumor response. Their main function is to identify specific antigens with cell surface immunoglobulin or B cell receptors [ 65 , 66 ]. As one of the most important components in the TME [ 67 ], macrophages can support tumor viability and survival by secreting immunosuppressive factors, cytokines and growth factors [ 68 ].…”