Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity.
Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity.
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DOI：
10.4049/jimmunol.0804074
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Wei WZ
中科院分区：
文献类型：
--
作者：
Jacob JB;Kong YC;Nalbantoglu I;Snower DP;Wei WZ
调节免疫系统以增强抗肿瘤免疫力会带来患自身免疫性疾病的风险，包括甲状腺功能减退症，正如接受免疫治疗方案临床试验的癌症患者所见。尽管人们倾向于将自身免疫视为癌症免疫治疗的积极指标，但一些自身免疫表现可能会危及生命，并且需要长期的医疗干预或从试验中剔除。我们建立了小鼠测试模型，通过同时监测肿瘤相关大鼠 erbB-2 (neu) 和另一种自身 Ag、小鼠甲状腺球蛋白 (mTg) 的免疫反应性来评估此类风险。我们之前报道过，在野生型抗甲状腺炎 BALB/c 小鼠中，在调节性 T 细胞 (Treg) 耗竭后经历了 neu+ TUBO 肿瘤的消退，对大鼠 neu 和 mTg 的免疫反应均得到增强，从而导致自身免疫性甲状腺炎 (EAT)。在这项研究中，我们在新转基因 BALB NeuT 雌性小鼠中测试了肿瘤免疫和自身免疫之间的平衡。首先，在用 CD25 mAb 消除 Tregs 和/或 DNA 疫苗接种治疗的 neu 耐受小鼠中，比较 neu+ 肿瘤的生长和进展。只有消除 Treg 并接种 neu DNA 疫苗才能消除对 neu 的耐受性，从而使 neu+ 肿瘤完全消退，并长期保护 58% 的小鼠免于自发肿瘤发生。然后通过使用或不使用 LPS 作为佐剂的合并 mTg 免疫来评估发生 EAT 的风险。在诱导肿瘤消退的小鼠中，mTg 反应随着 EAT 发育的适度增加而增强。因此，Treg 耗竭和 DNA 疫苗接种诱导的肿瘤消退会加剧自身免疫，这需要在免疫治疗期间密切监测。
Modulation of the immune system to amplify anti-tumor immunity carries the risk of developing autoimmune diseases, including hypothyroidism, as seen with cancer patients undergoing clinical trials for immunotherapeutic regimens. Although there is a tendency to view autoimmunity as a positive indicator for cancer immunotherapy, some autoimmune manifestations can be life-threatening and necessitate prolonged medical intervention or removal from trial. We have established murine test models to assess such risks by monitoring, simultaneously, the immune reactivity to tumor-associated rat erbB-2 (neu) and another self Ag, mouse thyroglobulin (mTg). We previously reported that in wild-type, thyroiditis-resistant BALB/c mice that underwent regression of neu+ TUBO tumors following regulatory T cell (Treg) depletion, immune responses to rat neu and mTg with resultant autoimmune thyroiditis (EAT) were both enhanced. In this study, we tested the balance between tumor immunity and autoimmunity in neu-transgenic BALB NeuT female mice. First, growth and progression of neu+ tumor were compared in neu tolerant mice treated with either CD25 mAb to deplete Tregs and/or DNA vaccination. Only Treg depletion followed by neu DNA vaccination abrogated tolerance to neu, resulting in complete regression of neu+ tumors, as well as long-term protection from spontaneous tumorigenesis in 58% of mice. The risk of developing EAT was then assessed by incorporated mTg immunization with or without LPS as adjuvant. In mice with induced tumor regression, mTg response was enhanced with modest increases in EAT development. Therefore, tumor regression induced by Treg depletion and DNA vaccination can exacerbate autoimmunity, which warrants close monitoring during immunotherapy.
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