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

Gunjan Mandal, Subir Biswas, Carmen M. Anadon, Xiaoqing Yu, Chandler D. Gatenbee, Sandhya Prabhakaran, Kyle K. Payne, Ricardo A. Chaurio, Alexandra Martin, Patrick Innamarato, Carlos Moran, John J. Powers, Carly M. Harro, Jessica A. Mine, Kimberly B. Sprenger, Kristen E. Rigolizzo, Xuefeng Wang, Tyler J. Curiel, Paulo C. Rodriguez, Alexander R. AndersonOzlen Saglam, Jose R. Conejo-Garcia

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)859-871
Number of pages13
JournalCancer Research
Volume82
Issue number5
DOIs
StatePublished - Mar 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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