TY - JOUR
T1 - The Efficacy of Targeted Monoclonal IgA Antibodies Against Pancreatic Ductal Adenocarcinoma
AU - Raymakers, Léon
AU - Passchier, Elsemieke M
AU - Verdonschot, Meggy E L
AU - Evers, Mitchell
AU - Chan, Chilam
AU - Kuijpers, Karel C
AU - Raicu, G Mihaela
AU - Molenaar, I Quintus
AU - van Santvoort, Hjalmar C
AU - Strijbis, Karin
AU - Intven, Martijn P W
AU - Daamen, Lois A
AU - Leusen, Jeanette H W
AU - Olofsen, Patricia A
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/4/24
Y1 - 2025/4/24
N2 - The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation.
AB - The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation.
KW - Antibodies, Monoclonal/therapeutic use
KW - Antigens, Neoplasm/metabolism
KW - CD47 Antigen/metabolism
KW - Carcinoma, Pancreatic Ductal/immunology
KW - Cell Line, Tumor
KW - Epithelial Cell Adhesion Molecule/metabolism
KW - Humans
KW - Immunoglobulin A/immunology
KW - Immunotherapy
KW - Mucin-1/metabolism
KW - Neutrophils/immunology
KW - Pancreatic Neoplasms/immunology
KW - Tumor Microenvironment/drug effects
U2 - 10.3390/cells14090632
DO - 10.3390/cells14090632
M3 - Article
C2 - 40358156
SN - 2073-4409
VL - 14
JO - Cells
JF - Cells
IS - 9
M1 - 632
ER -