Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer
Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer
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DOI：
10.1158/0008-5472.can-05-0141
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Dubinett, SM
中科院分区：
文献类型：
--
作者：
Sharma, S;Yang, SC;Dubinett, SM
环氧合酶（考克斯）-2及其产物前列腺素（PG）E-2是免疫抑制网络的基础，在非小细胞肺癌的发病机制中起重要作用。CD 4（+）CD 25（+）调节性T细胞（Treg）在维持免疫自身耐受中起重要作用。CD 4（+）CD 25（+）Treg细胞活性在肺癌中增加，并且似乎在抑制抗肿瘤免疫应答中起作用。明确调节性T细胞活性的调控途径有助于我们理解宿主抗肿瘤免疫反应的局限性。肿瘤来源的考克斯-2/PGE（2）诱导Treg细胞特异性转录因子Foxp 3的表达，并增加Treg细胞活性。对E-前列腺素（EP）受体需求的评估显示，PGE（2）介导的Treg细胞Foxp 3基因表达的诱导在缺乏EP 4受体的情况下显著降低，在缺乏EP 2受体表达的情况下消除。在体内，考克斯-2抑制可以降低Treg细胞的频率和活性，减弱肿瘤浸润淋巴细胞中Foxp 3的表达，并降低肿瘤负荷。对接受考克斯-2抑制剂的小鼠转移Treg细胞或给予PGE（2）可逆转这些效应。我们的结论是，抑制考克斯-2/PGE（2）抑制Treg细胞活性并增强抗肿瘤反应。
Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E-2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. CD4(+)CD25(+) T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4(+)CD25(+) Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE(2) induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE(2)-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE(2) to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE(2) suppresses Treg cell activity and enhances antitumor responses.