Increased CD8+ T-cell function following castration and immunization is countered by parallel expansion of regulatory T cells.
Increased CD8+ T-cell function following castration and immunization is countered by parallel expansion of regulatory T cells.
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DOI：
10.1158/0008-5472.can-11-2499
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发表时间：
2012-04-15
期刊：
影响因子：
11.2
通讯作者：
Dubey P
中科院分区：
文献类型：
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作者：
Tang S;Moore ML;Grayson JM;Dubey P
虽然雄激素消融治疗在治疗原发性前列腺癌中是有效的，但大量患者发展为不可治愈的去势抵抗性疾病。最近的研究表明，疫苗接种和雄激素消融之间存在潜在的协同作用，但增强的T细胞功能是短暂的。使用确定的肿瘤抗原模型UV-8101-RE，我们发现伴随去势显著增加了野生型小鼠免疫后早期抗原特异性CD 8 + T细胞的频率和功能。然而，在免疫后的后期时间点，效应子功能降低到与未去势小鼠相同的水平，并伴随着免疫后CD 4 + CD 25 + Foxp 3+调节性T细胞（Treg）的扩增。我们研究了前列腺荷瘤小鼠去势后是否发生Treg扩增。在前列腺特异性Pten−/−小鼠前列腺癌模型中，我们观察到携带去势抵抗性内源性前列腺肿瘤的小鼠中Treg扩增加速，这阻止了对UV-8101-RE的效应反应。Treg耗竭与去势一起在Pten−/−小鼠中引发了对UV-8101-RE的强烈CD 8 + T细胞应答，并在去势和免疫的野生型小鼠中挽救了效应子功能。此外，Pten−/−小鼠的Treg扩增可通过体内白细胞介素（IL）-2阻断来阻止，这表明去势和免疫产生的IL-2增加可促进Treg扩增。因此，我们的研究结果表明，虽然效应器反应增强去势，伴随的扩展THBG是一种机制，负责后雄激素消融仅短暂的免疫增强。
Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested a potential synergy between vaccination and androgen ablation, yet the enhanced T-cell function is transient. Using a defined tumor antigen model, UV-8101-RE, we found that concomitant castration significantly increased the frequency and function of antigen-specific CD8+ T cells early after the immunization of wild-type mice. However, at a late time point after immunization, effector function was reduced to the same level as noncastrated mice and was accompanied by a concomitant amplification in CD4+CD25+Foxp3+ regulatory T cells (Treg) following immunization. We investigated whether Treg expansion occurred following castration of prostate tumor–bearing mice. In the prostate-specific Pten−/− mouse model of prostate cancer, we observed an accelerated Treg expansion in mice bearing the castration-resistant endogenous prostate tumor, which prevented effector responses to UV-8101-RE. Treg depletion together with castration elicited a strong CD8+ T-cell response to UV-8101-RE in Pten−/− mice and rescued effector function in castrated and immunized wild-type mice. In addition, Treg expansion in Pten−/− mice was prevented by in vivo interleukin (IL)-2 blockade suggesting that increased IL-2 generated by castration and immunization promotes Treg expansion. Our findings therefore suggest that although effector responses are augmented by castration, the concomitant expansion of Tregs is one mechanism responsible for only transient immune potentiation after androgen ablation.