Enzler Thomas, Shi Jiaqi, McGue Jake, Griffith Brian D, Sun Lei, Sahai Vaibhav, Nathan Hari, Frankel Timothy L
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Int J Mol Sci. 2024 Mar 3;25(5):2953. doi: 10.3390/ijms25052953.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8 T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8 T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8 T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA.
胰腺导管腺癌（PDAC）是一种极具毁灭性的疾病，5年生存率仅为12.5%。PDAC主要起源于非囊性胰腺上皮内瘤变（PanIN）和囊性导管内乳头状黏液性肿瘤（IPMN）。我们运用多重免疫荧光和计算机成像技术对PDAC及其前驱病变的免疫微环境（IME）进行表征、定位和比较。我们发现，IPMN的IME中大量浸润了CD8 T细胞和PD-L1阳性抗原呈递细胞（APC），而PanIN的IME中CD8 T细胞较少，PD-L1阳性APC也较少，但免疫抑制性调节性T细胞（Treg）数量增加。因此，IPMN和PanIN中的免疫抑制似乎是由不同机制介导的。IPMN中的免疫抑制是由APC上的PD-L1表达促成的，而Treg似乎在PanIN中起关键作用。我们的研究结果提示了针对高危前驱病变的潜在免疫治疗干预措施，即在IPMN中靶向PD-1/PD-L1，在PanIN中靶向CTLA-4阳性Treg，以恢复免疫监视并防止进展为癌症。正如在PDAC中观察到的那样，Treg随着恶性转化而积累，在IPMN相关的PDAC（IAPA）中积累程度较轻。PDAC微环境中大量的Treg与CD8 T细胞和癌上皮细胞（EC）之间的相互作用显著减少相关，突出了Treg作为PDAC免疫抑制关键参与者的重要性。我们发现有证据表明，抗原呈递缺陷因APC上的PD-L1表达而进一步加重，这可能导致IAPA中的免疫抑制，提示PD-L1/PD-1免疫检查点抑制剂在IAPA治疗中的作用。
