PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest forms of cancer with very few treatment options. The 5-year survival rate for PDAC is 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, and Cdh11 inhibition significantly extended survival in mice with PDAC. However, the mechanisms by which Cdh11 deficiency influences PDAC progression and anti-tumor immune responses have yet to be fully elucidated. To investigate Cdh11-deficiency induced changes in PDAC tumor microenvironment (TME), we crossed p48-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice with Cdh11+/- mice and performed single-cell RNA sequencing (scRNA-seq) of the non-immune (CD45-) and immune (CD45+) compartment of KPC tumor-bearing Cdh11 proficient (KPC-Cdh11+/+) and Cdh11 deficient (KPC-Cdh11+/-) mice. Our analysis showed that Cdh11 is expressed primarily in cancer-associated fibroblasts (CAFs) and at low levels in epithelial cells undergoing epithelial-to-mesenchymal transition (EMT). Cdh11 deficiency altered the molecular profile of CAFs, leading to a decrease in the expression of myofibroblast markers such as Acta2 and Tagln and cytokines such as Il6, Il33 and Midkine (Mdk). We also observed a significant decrease in the presence of monocytes/macrophages and neutrophils in KPC-Cdh11+/- tumors while the proportion of T cells was increased. Additionally, myeloid lineage cells from Cdh11-deficient tumors had reduced expression of immunosuppressive cytokines that have previously been shown to play a role in immune suppression. In summary, our data suggests that Cdh11 deficiency significantly alters the fibroblast and immune microenvironments and contributes to the reduction of immunosuppressive cytokines, leading to an increase in anti-tumor immunity and enhanced survival.
摘要：
胰腺导管腺癌（PDAC）是五种最致命的癌症之一，治疗选择很少。诊断后PDAC的5年生存率为10％。钙粘蛋白11（Cdh11），细胞间粘附分子,有人建议在PDAC中促进肿瘤生长和免疫抑制，和Cdh11抑制可显着延长PDAC小鼠的生存期。然而,Cdh11缺乏影响PDAC进展和抗肿瘤免疫反应的机制尚未完全阐明。研究Cdh11缺乏引起的PDAC肿瘤微环境（TME）的变化，我们将p48-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+(KPC)小鼠与Cdh11+/-小鼠杂交,并对KPC荷瘤h11的非免疫(CD45-)和免疫(CD45+)区室进行单细胞RNA测序(scRNA-seq)(KPC-Cdh11+/CdPC缺陷小鼠)。我们的分析表明，Cdh11主要在癌症相关成纤维细胞（CAF）中表达，而在经历上皮-间质转化（EMT）的上皮细胞中表达水平较低。Cdh11缺乏改变了CAFs的分子谱，导致肌成纤维细胞标志物如Acta2和Tagln和细胞因子如Il6、Il33和Midkine(Mdk)的表达降低。我们还观察到KPC-Cdh11+/-肿瘤中单核细胞/巨噬细胞和嗜中性粒细胞的存在显著减少,而T细胞的比例增加。此外,来自Cdh11缺陷肿瘤的髓系细胞的免疫抑制细胞因子的表达降低，这些细胞因子先前已被证明在免疫抑制中起作用。总之,我们的数据表明，Cdh11缺乏显着改变成纤维细胞和免疫微环境，并有助于减少免疫抑制细胞因子，导致抗肿瘤免疫力的提高和生存率的提高。
