Harper Megan M, Lin Miranda, Qasem Shadi A, Patel Reema A, Cavnar Michael J, Pandalai Prakash K, Gao Mei, Kim Joseph
Division of Surgical Oncology, University of Kentucky, Lexington, KY 40536, USA.
Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA.
Cancers (Basel). 2022 Jun 21;14(13):3051. doi: 10.3390/cancers14133051.
We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.
我们最近证明，免疫检查点PD-1在胰腺导管腺癌（PDAC）细胞中内源性表达。我们的数据表明，PD-1蛋白并非免疫细胞所特有，癌细胞具有未被识别的内在信号转导级联反应。基于这一范式转变，我们试图进一步表征PDAC中PD-1的表达。我们利用磷酸化探索者阵列来鉴定由PD-1信号上调的通路。我们发现PD-1介导的PDAC细胞中原癌基因MET的激活，这依赖于肝细胞生长因子（MET配体），而非直接蛋白质相互作用的结果。然后我们发现，PDAC细胞中的PD-1/MET轴调节生长、迁移和侵袭。重要的是，PD-1/MET轴诱导上皮-间质转化（EMT），这是PDAC中一个公认的早期致癌过程。我们观察到，联合靶向PDAC细胞的PD-1和MET可在PDAC细胞系、患者来源的类器官和患者来源的异种移植模型中产生显著的直接肿瘤细胞细胞毒性并抑制生长，且不依赖细胞毒性免疫反应。这是关于PDAC内源性PD-1表达调节MET信号的首次报道，基于我们越来越多的研究工作，表明PDAC细胞中PD-1表达的致癌表型与其免疫原性作用不同。这些结果凸显了一种范式转变，即肿瘤特异性PD-1轴是通过拮抗先前未被识别的PD-1依赖性致癌途径有效杀死PDAC细胞的新靶点。
