Raymakers Léon, Passchier Elsemieke M, Verdonschot Meggy E L, Evers Mitchell, Chan Chilam, Kuijpers Karel C, Raicu G Mihaela, Molenaar I Quintus, van Santvoort Hjalmar C, Strijbis Karin, Intven Martijn P W, Daamen Lois A, Leusen Jeanette H W, Olofsen Patricia A
Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Division of Imaging & Oncology, University Medical Center Utrecht Cancer Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Cells. 2025 Apr 24;14(9):632. doi: 10.3390/cells14090632.
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.
免疫疗法在胰腺导管腺癌（PDAC）中的疗效仍然有限。肿瘤微环境（TME）以包括中性粒细胞在内的抑制性髓系细胞的积累为特征，这是PDAC免疫治疗耐药的原因。IgA单克隆抗体（mAbs）可以激活中性粒细胞以杀死肿瘤细胞；通过阻断髓系免疫检查点CD47可进一步增强这种作用。在本研究中，我们调查了这种治疗策略对PDAC的潜力。我们测定了肿瘤相关抗原（TAAs）在PDAC细胞系和新鲜患者样本上的表达，结果显示TAAs上皮细胞粘附分子（EpCAM）、滋养层细胞表面抗原2（TROP2）和粘蛋白-1（MUC1）以及CD47在PDAC上持续表达。与此一致的是，我们表明抗EpCAM的IgA mAbs可以激活中性粒细胞以裂解各种PDAC细胞系和肿瘤细胞，添加CD47阻断剂可增强这种作用。此外，我们观察到患者肿瘤中存在中性粒细胞并表达IgA受体。总之，我们的结果表明，IgA mAb与CD47阻断剂联合使用是一种有前景的PDAC临床前治疗策略，值得进一步研究。
