CCR4 blockade leads to clinical activity and prolongs survival in a canine model of advanced prostate cancer.
CCR4 blockade leads to clinical activity and prolongs survival in a canine model of advanced prostate cancer.
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CCR4 阻断可在晚期前列腺癌的犬模型中产生临床活性并延长生存期。
DOI：
10.1101/2021.04.12.439476
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Yasuyuki M.
中科院分区：
文献类型：
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作者：
Shingo Maeda;Tomoki Motegi;Aki Iio;Kenjiro Kaji;Yuko Goto-Koshino;Shotaro Eto;Namiko Ikeda;Takayuki Nakagawa;Ryohei Nishimura;Tomohiro Yonezawa;Yasuyuki M.
靶向调节性T细胞（Treg）浸润是癌症免疫治疗的新兴策略。然而，这种策略在晚期前列腺癌中的疗效仍不清楚。在这里，我们描述了这种策略在晚期前列腺癌犬模型中的治疗效果。我们使用患有自然发生的前列腺癌的狗来研究Treg浸润到肿瘤组织中的分子机制以及抗Treg治疗的效果。我们发现，肿瘤浸润性甲状腺肿与患有自发性前列腺癌的狗预后不良相关。RNA测序和蛋白质分析表明，Treg浸润是由肿瘤产生趋化因子CCL 17和TcR上表达的受体CCR 4之间的相互作用介导的。患有晚期前列腺癌的狗对靶向CCR 4的单克隆抗体mogamulizumab有反应，存活率提高，临床相关不良事件的发生率低。探索性分析显示尿CCL 17浓度和BRAFV 595 E突变独立预测对mogamulizumab的应答。对公开可用的人类前列腺癌转录组数据集的分析显示，CCL 17/CCR 4轴与Treg标志物Foxp 3相关。计算机生存分析显示，CCL 17的高表达与不良预后相关。免疫组织化学证实，肿瘤浸润性TCR 4表达在人类前列腺癌患者。这些发现表明，通过阻断CCR 4进行抗Treg治疗是治疗晚期前列腺癌的一种很有前途的方法。一句话总结在犬前列腺癌模型中，通过阻断CCR 4靶向调节性T细胞浸润诱导客观反应并提高生存率。
Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, the efficacy of this strategy in advanced prostate cancer remains unclear. Here, we describe the therapeutic efficacy of this strategy in a canine model of advanced prostate cancer. We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration into tumor tissues and the effect of anti-Treg treatment. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed that Treg infiltration was mediated by interaction between the tumor-producing chemokine, CCL17, and the receptor CCR4 expressed on Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with improved survival and low incidence of clinically relevant adverse events. Exploratory analyses showed urinary CCL17 concentration and BRAFV595Emutation to be independently predictive of the response to mogamulizumab. Analysis of a publicly available transcriptomic dataset of human prostate cancer showed that the CCL17/CCR4 axis correlated with the Treg marker, Foxp3. In silico survival analyses showed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. These findings suggest that anti-Treg treatment through the blocking of CCR4 is a promising therapeutic approach for advanced prostate cancer.One Sentence SummaryTargeting regulatory T cell infiltration by CCR4 blockade induces objective responses and improves survival in a canine model of prostate cancer.