Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England.
Gastroenterology. 2013 Nov;145(5):1121-32. doi: 10.1053/j.gastro.2013.07.025. Epub 2013 Jul 25.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells.
We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes.
Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase(+) and CD68(+) cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8(+), FoxP3(+), CD56(+), or CD20(+) cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8(+) T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8(+) T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA.
Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response.
胰腺导管腺癌（PDAC）的特征是存在富含多种不同免疫细胞的显著纤维母细胞性微环境。活化的胰腺星状细胞（PSCs）有助于纤维母细胞形成。我们研究了不同的基质隔室是否被不同类型的免疫细胞浸润。
我们使用组织微阵列分析比较了不同胰胆管疾病组织（PDAC、壶腹癌、胆管癌、黏液性囊腺瘤、慢性炎症和慢性胰腺炎）以及肿瘤旁基质（距肿瘤<100 μm）和全基质隔室的免疫细胞浸润。我们研究了免疫浸润与患者生存时间之间的关联。我们还分析了 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre（KPC）小鼠中的 T 细胞迁移和肿瘤浸润，以及全反式维甲酸（ATRA）对这些过程的影响。
来自 2 组独立患者的 PDAC 样本的肿瘤旁隔室中髓过氧化物酶（+）和 CD68（+）细胞的数量高于全基质隔室。然而，与胆管癌和壶腹癌不同，PDAC 的肿瘤旁隔室中 CD8（+）、FoxP3（+）、CD56（+）或 CD20（+）细胞的数量少于全基质隔室。PDAC 患者肿瘤旁隔室中 CD8（+）T 细胞密度较高者的生存时间长于密度较低者。在 KPC 小鼠中，给予 ATRA（可使 PSCs 静止）可增加肿瘤旁隔室中 CD8（+）T 细胞的数量。我们发现活化的 PSCs 表达细胞因子、趋化因子和黏附分子，这些分子可调节 T 细胞迁移。体外迁移实验表明，与静止的 PSCs 或肿瘤细胞相比，来自 PDAC 患者的 CD8（+）T 细胞向分泌 CXCL12 的活化 PSCs 的趋化性增加。这些作用可以通过 CXCL12 的敲低或 PSCs 用 ATRA 处理来逆转。
基于对 PDAC 患者样本和 KPC 小鼠的研究，活化的 PSCs 似乎可减少 CD8（+）T 细胞向肿瘤旁基质隔室的迁移，从而阻止其接近癌细胞。活化的 PSCs 失调的信号转导可能会阻止有效的抗肿瘤免疫反应。
