Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.
Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.
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DOI：
10.1084/jem.20101876
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发表时间：
2011-03-14
期刊：
影响因子：
--
通讯作者：
Protti MP
中科院分区：
文献类型：
--
作者：
De Monte L;Reni M;Tassi E;Clavenna D;Papa I;Recalde H;Braga M;Di Carlo V;Doglioni C;Protti MP
胰腺癌中TSLP的表达与抗肿瘤免疫的Th 2偏离相关，而Th 2偏离与患者生存率降低相关。胰腺癌是一种非常侵袭性的疾病，其特征在于显著的结缔组织增生，其中Th 2（加塔-3+）淋巴浸润超过Th 1（T-bet+）淋巴浸润。我们发现加塔-3+/T-bet+肿瘤浸润淋巴样细胞的比率是患者存活的独立预测标志物。手术治疗的IB/III期疾病患者的比例低于中位数，总生存期延长具有统计学意义，这意味着Th 2应答在疾病进展中起积极作用。胸腺基质淋巴细胞生成素（Thymic stromal lymphopoietin，TSLP）是由肿瘤相关成纤维细胞（CAFs）经肿瘤坏死因子α（tumor necrosis factor α，TNF α）和白细胞介素1β（interleukin 1β，IL-1β）激活后分泌的，通过骨髓树突状细胞（myeloid dendritic cell，DC）调节促进Th 2细胞极化。TSLP的上清液激活CAFs诱导体外髓样DCs上调TSLP受体（TSLPR），分泌Th 2吸引趋化因子，并获得TSLP依赖的Th 2极化能力在体外。在体内，Th 2趋化因子在肿瘤和间质中表达，TSLPR表达DC存在于肿瘤间质和肿瘤引流淋巴结中，但不存在于非引流淋巴结中。总的来说，这项研究确定了胰腺癌中肿瘤细胞和CAF之间的串扰，导致TSLP依赖性诱导Th 2型炎症，这与患者生存率降低有关。因此，阻断CAFs产生TSLP可能有助于改善胰腺癌的预后。
Expression of TSLP in pancreatic cancer correlates with Th2 deviation of antitumor immunity that is associated with decrease of patient survival. Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.
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影响因子：
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