Regulatory T cells in ovarian cancer: Biology and therapeutic potential
Regulatory T cells in ovarian cancer: Biology and therapeutic potential
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DOI：
10.1111/j.1600-0897.2005.00330.x
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发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Curiel, TJ
中科院分区：
文献类型：
--
作者：
Barnett, B;Kryczek, I;Curiel, TJ
肿瘤表达肿瘤相关抗原（TAA），因此应该是免疫攻击的目标。尽管如此，自发清除已建立的肿瘤是罕见的。(1)许多工作已经证明，肿瘤有许多策略来防止TAA的呈递，或在T细胞共信号分子的背景下防止TAA呈递。（1，2）因此，人们认为缺乏TAA特异性免疫在很大程度上是一个被动过程：肿瘤只是没有提供足够的TAA，或者抗原呈递细胞没有足够的刺激能力。在此基础上，尝试通过使用最佳抗原呈递细胞或通过离体培养TAA特异性效应T细胞随后过继转移来支持TAA特异性免疫。(3)这些方法在人类肿瘤的小鼠模型中取得了一些成功，并在人体试验中显示出一些早期临床疗效，尽管长期疗效仍有待确定，并且后勤问题相当严重。(4)这些研究确立了实验诱导的TAA特异性免疫是治疗癌症（包括卵巢癌）的合理且潜在有效的手段的概念。尽管如此，最近的工作表明，缺乏自然诱导的TAA特异性免疫不仅仅是一个被动的过程。（5-12）我们讨论了最近的数据，这些数据清楚地表明“肿瘤通过诱导TAA特异性耐受积极地阻止TAA特异性免疫的诱导”。(13)这种耐受性部分由调节性T细胞（Tcells）介导。逆转这些耐受性条件的方法代表了一种新的抗癌治疗策略。我们在这方面讨论了人类卵巢癌中的Treg，并提出了证据表明，使用地尼白介素diftitox（Ontak）消除人类癌症（包括卵巢癌）中的Treg，可提高免疫力，并可能具有治疗作用。
Tumors express tumor-associated antigens (TAA) and thus should be the object of immune attack. Nonetheless, spontaneous clearance of established tumors is rare.(1) Much work has demonstrated that tumors have numerous strategies either to prevent presentation of TAA, or to prevent TAA presentation in the context of T-cell co-signaling molecules.(1,2) Thus, it was thought that lack of TAA-specific immunity was largely a passive process: tumors simply did not present enough TAA, or antigen-presenting cells did not have sufficient stimulatory capacity. On this basis, attempts were made to bolster TAA-specific immunity by using optimal antigen-presenting cells or by growing TAA-specific effector T cells ex vivo followed by adoptive transfer.(3) These approaches met with some success in mouse models of human tumors, and showed some early clinical efficacy in human trials, although long-term efficacy remains to be established, and logistical problems are considerable.(4) These studies established the concept that experimentally induced TAA-specific immunity is a rational and potentially efficacious means to treat cancer, including ovarian cancer. Nonetheless, recent work demonstrates that lack of naturally induced TAA-specific immunity is not simply a passive process.(5-12) We discuss recent data clearly demonstrating that 'tumors actively prevent induction of TAA-specific immunity through induction of TAA-specific tolerance'.(13) This tolerance is mediated in part by regulatory T cells (Tregs). Means to revert these tolerizing conditions represent a novel anticancer therapeutic stratagem. We discuss Tregs in this regard in human ovarian cancer and present evidence that depleting Treg in human cancer, including ovarian cancer, using denileukin diftitox (Ontak), improves immunity and may be therapeutic.