Balancing between Antitumor Efficacy and Autoimmune Pathology in T-Cell-Mediated Targeting of Carcinoembryonic Antigen
Balancing between Antitumor Efficacy and Autoimmune Pathology in T-Cell-Mediated Targeting of Carcinoembryonic Antigen
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DOI：
10.1158/0008-5472.can-08-1864
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Offringa, Rienk
中科院分区：
文献类型：
--
作者：
Bos, Rinke;van Duikeren, Suzanne;Offringa, Rienk
癌胚抗原(CEA)作为结直肠癌免疫治疗的潜在靶点被广泛研究。虽然CEA在肿瘤中过度表达，但在正常组织中也有表达，这引发了人们对CEA靶向免疫治疗的可行性和安全性的质疑。我们在转基因小鼠中研究了这些问题，在转基因小鼠中，人CEA在正常组织中的表达与人类非常相似。我们的数据显示，这些小鼠的T细胞对CEA的反应因胸腺和外周耐受而减弱。因此，有效的肿瘤靶向只能通过过继转移来自不耐受供者的T细胞，并结合消除外周免疫调节机制的干预来实现。然而，这样的治疗可能会导致严重的肠道自身免疫病理，与体重减轻和死亡相关。有趣的是，通过耗尽T调节细胞对受体小鼠进行预适应，可以在没有毒性的情况下实现免疫介导的肿瘤控制。在这种情况下，CEA特异的T细胞反应低于中毒方案诱导的反应，并伴随着针对非自身抗原的额外T细胞反应。这些发现说明了在临床前体内模型中测试针对CEA等自身抗原的过继免疫疗法的重要性，并表明免疫干预方案的选择至关重要地决定了治疗效果和毒性之间的平衡。[癌症资源2008；68(20)：8446-55]
Carcinoembryonic antigen (CEA) is intensively studied as a potential target for immunotherapy of colorectal cancers. Although overexpressed by tumors, CEA is also expressed in normal tissues, raising questions about the feasibility and safety of CEA-targeted immunotherapy. We investigated these issues in transgenic mice in which the expression of human CEA in normal tissues closely resembles that in man. Our data show that the T-cell response against CEA in these mice is blunted by both thymic and peripheral tolerance. Consequently, effective tumor targeting is only achieved by adoptive transfer of T cells from nontolerant donors in combination with interventions that eliminate peripheral immune regulatory mechanisms. However, such treatments can result in severe intestinal autoimmune pathology associated with weight loss and mortality. Interestingly, preconditioning of recipient mice by depletion of T-regulatory cells results in immune-mediated tumor control in the absence of toxicity. In this setting, CEA-specific T-cell responses are lower than those induced by toxic regimens and accompanied by additional T-cell responses against non-self antigen. These findings illustrate the importance of testing adoptive immunotherapies targeting self antigens such as CEA in preclinical in vivo models and show that the choice of immune intervention regimen critically determines the balance between therapeutic efficacy and toxicity. [Cancer Res 2008;68(20):8446-55]