Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis.
Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis.
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DOI：
10.1158/0008-5472.can-16-2565
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发表时间：
2017-06-15
期刊：
影响因子：
11.2
通讯作者：
Leung HY
中科院分区：
文献类型：
--
作者：
Loveridge CJ;Mui EJ;Patel R;Tan EH;Ahmad I;Welsh M;Galbraith J;Hedley A;Nixon C;Blyth K;Sansom O;Leung HY
前列腺癌 (PCa) 似乎对免疫检查点疗法没有反应，其中 T 细胞浸润可能是一个关键的限制因素。在这里，我们报告了证据表明，在已建立的 Pten 缺陷型小鼠 PCa 模型中，消除生长调节激酶 Erk5 可以增加 T 细胞浸润。与对照 Pten 突变小鼠相比，前列腺组织中 Pten 和 Erk5（前列腺 DKO）双重突变的小鼠表现出中位生存期显着增加，肿瘤大小和增殖减少，后者表现出 Erk5 mRNA 表达增加。比较转录组分析揭示了前列腺 DKO 小鼠中趋化因子 Ccl5 和 Cxcl10 的上调，这是两种有效的 T 淋巴细胞趋化因子。与这种效应一致，我们观察到 DKO 小鼠肿瘤的前列腺上皮和基质中以 CD4+ T 细胞为主的浸润相对增加。总的来说，我们的结果为 ERK5 作为增强前列腺癌 T 细胞浸润的靶标提供了临床前概念证明，可能对利用免疫疗法治疗这种疾病产生影响。
Prostate cancer (PCa) does not appear to respond to immune checkpoint therapies where T cell infiltration may be a key limiting factor. Here we report evidence that ablating the growth regulatory kinase Erk5 can increase T cell infiltration in an established Pten-deficient mouse model of human PCa. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared to control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4+ T cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease.