In situ vaccination combined with androgen ablation and regulatory T-cell depletion reduces castration-resistant tumor burden in prostate-specific pten knockout mice.
In situ vaccination combined with androgen ablation and regulatory T-cell depletion reduces castration-resistant tumor burden in prostate-specific pten knockout mice.
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DOI：
10.1158/0008-5472.can-09-2490
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Dubey P
中科院分区：
文献类型：
--
作者：
Akins EJ;Moore ML;Tang S;Willingham MC;Tooze JA;Dubey P
There is no effective treatment for prostate cancer arising after androgen ablation. Previous studies have analyzed the short-term effects of androgen ablation on the immune system and suggest an abatement of immune suppression by hormone removal. Since castration-resistant disease can arise years after treatment, it is crucial to determine the duration of immune potentiation by castration. Because immunotherapeutic efficacy is determined by the balance of immune cell subsets and their location within the tumor, we assessed the acute and chronic effect of androgen ablation on the localization of T cell subsets within castration-resistant murine prostate cancer. We observed a transient increase in CD4+ and CD8+ T cell numbers at the residual tumor after androgen ablation. More than two months later, regulatory T cells were increasingly within prostate epithelium, while cytolytic T cells (CTL), which were evenly distributed prior to androgen ablation, became sequestered within stroma. Anti-CD25 antibody administration along with castration enhanced CTL access to cancerous glands, but did not increase effector function. Intra-prostatic injection of LIGHT-expressing tumor cells increased the proportion of CD8+ T cells with functional capacity within the cancerous gland. In addition, Treg depletion within the tumor was enhanced. Together these manipulations significantly reduced castration-resistant tumor burden. Thus, our results indicate that immune modulations which prevent Treg accumulation and augment effector cell infiltration of prostatic epithelium may be effective in reducing tumor burden or preventing tumor recurrence after androgen ablation therapy.
