TY - JOUR
T1 - IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer
AU - Mandal, Gunjan
AU - Biswas, Subir
AU - Anadon, Carmen M.
AU - Yu, Xiaoqing
AU - Gatenbee, Chandler D.
AU - Prabhakaran, Sandhya
AU - Payne, Kyle K.
AU - Chaurio, Ricardo A.
AU - Martin, Alexandra
AU - Innamarato, Patrick
AU - Moran, Carlos
AU - Powers, John J.
AU - Harro, Carly M.
AU - Mine, Jessica A.
AU - Sprenger, Kimberly B.
AU - Rigolizzo, Kristen E.
AU - Wang, Xuefeng
AU - Curiel, Tyler J.
AU - Rodriguez, Paulo C.
AU - Anderson, Alexander R.
AU - Saglam, Ozlen
AU - Conejo-Garcia, Jose R.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-2376
DO - 10.1158/0008-5472.CAN-21-2376
M3 - Article
C2 - 34949671
AN - SCOPUS:85125744350
SN - 0008-5472
VL - 82
SP - 859
EP - 871
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -