Mu Kaiyi, Fu Juan, Gai Jessica, Ravichandran Harshitha, Zheng Lei, Sun Wei-Chih
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ann Pancreat Cancer. 2023 Nov;6(10). doi: 10.21037/apc-23-13. Epub 2023 Nov 20.
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is highly metastatic. Our prior studies have demonstrated the critical role of axon guidance pathway genes in PDAC and the connection between neuronal development and the tumor microenvironment. A recent study newly identified 20 neuronal development genes [disks large homolog 2 (), neuron-glial-related cell adhesion molecule (), neurexin3 (), mitogen-activated protein kinase 10 (), platelet-derived growth factor D (), protein kinase C epsilon (), potassium calcium-activated channel subfamily M alpha 1 (), polycystic kidney and hepatic disease 1 (), neural cell adhesion molecule 1 (), neuregulin-1 (), zinc finger protein 667 (), cystic fibrosis transmembrane conductance regulator (), acyl-CoA medium-chain synthetase-3 (), complement 6 (), protein tyrosine phosphatase receptor type M (), hypoxia-inducible factor 1 alpha (), adenylyl cyclase 5 (), adherens junctions-associated protein 1 (), neurobeachin (), sodium voltage-gated channel alpha subunit 9 ()] that are associated with perineural invasion and poor prognosis of PDAC. The relationship between genetic alterations in these 20 genes and tumor immune microenvironment (TME) has not previously been investigated.
We hence applied the sequential multiplex immunohistochemistry results of biopsy specimens from 63 PDAC patients to investigate this relationship.
We found that, except for and , genetic alterations involving these 20 genes are associated with significant changes in the densities of major immune cell subtypes. Except for , the copy number loss involving this panel of neuronal development genes is significantly associated with changes in immune cell infiltrates. In contrast, the copy number gain in fewer genes, including , , , , , , and , is significantly associated with changes in immune cell infiltrates.
Our study suggested that neuronal development genes play a role in modulating TME in a pancreatic cancer setting.
胰腺导管腺癌（PDAC）预后较差，且具有高度转移性。我们之前的研究已经证明轴突导向通路基因在PDAC中的关键作用以及神经元发育与肿瘤微环境之间的联系。最近一项研究新鉴定出20个神经元发育基因[盘大同源蛋白2（）、神经胶质相关细胞粘附分子（）、神经连接蛋白3（）、丝裂原活化蛋白激酶10（）、血小板衍生生长因子D（）、蛋白激酶Cε（）、钾钙激活通道亚家族Mα1（）、多囊肾和肝病1（）、神经细胞粘附分子1（）、神经调节蛋白-1（）、锌指蛋白667（）、囊性纤维化跨膜传导调节因子（）、酰基辅酶A中链合成酶-3（）、补体6（）、蛋白酪氨酸磷酸酶受体M型（）、缺氧诱导因子1α（）、腺苷酸环化酶5（）、粘着连接相关蛋白1（）、神经海滩蛋白（）、钠电压门控通道α亚基9（）]，它们与PDAC的神经周围浸润和不良预后相关。此前尚未研究这20个基因的基因改变与肿瘤免疫微环境（TME）之间的关系。
因此，我们应用63例PDAC患者活检标本的连续多重免疫组化结果来研究这种关系。
我们发现，除了和，涉及这20个基因的基因改变与主要免疫细胞亚型密度的显著变化相关。除了，涉及这一组神经元发育基因的拷贝数缺失与免疫细胞浸润的变化显著相关。相比之下，包括、、、、、和在内的较少基因的拷贝数增加与免疫细胞浸润的变化显著相关。
我们的研究表明，神经元发育基因在胰腺癌环境中调节TME方面发挥作用。
