Cancer-FOXP3 directly activated CCL5 to recruit FOXP3(+)Treg cells in pancreatic ductal adenocarcinoma.
Cancer-FOXP3 directly activated CCL5 to recruit FOXP3(+)Treg cells in pancreatic ductal adenocarcinoma.
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Cancer-FOXP3直接激活CCL5在胰腺导管腺癌中招募FOXP3 Treg细胞
作者：
Wang X;Lang M;Zhao T;Feng X;Zheng C;Huang C;Hao J;Dong J;Luo L;Li X;Lan C;Yu W;Yu M;Yang S;Ren H
叉头盒蛋白3（FOXP 3）最初被鉴定为调节性T细胞（Treg细胞）的关键转录因子，也在包括胰腺导管腺癌（PDAC）在内的许多肿瘤中表达。然而，其在PDAC进展中的作用仍然难以捉摸。在本研究中，我们利用120例PDAC根治性切除后的组织，通过免疫组化检测癌FOXP 3和Treg细胞，并评估这些患者的临床和病理特征。癌症-FOXP 3与PDAC患者肿瘤组织中Treg细胞积聚呈正相关。此外，高癌症FOXP 3表达与PDAC中肿瘤体积增加和预后不良相关，特别是与高水平Treg细胞相结合。癌症FOXP 3的过表达促进了免疫活性同基因小鼠的肿瘤生长，但在免疫功能低下或Treg细胞耗尽的小鼠中则没有。此外，CCL 5直接被癌症-FOXP 3反式激活，并在体外和体内促进外周血Treg细胞向肿瘤部位的募集。这一发现进一步得到了以下证据的加强：癌症-FOXP 3的Treg细胞募集受到CCL 5中和的损害，从而抑制PDAC的生长。总之，癌症-FOXP 3通过直接反式激活CCL 5募集Treg细胞，作为预后生物标志物和免疫抑制微环境的关键决定因素。因此，cancer-FOXP 3可用于选择对CCL 5/CCR 5阻断免疫治疗具有更好应答的患者。
Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy.