CD8+ T cells promote proliferation of benign prostatic hyperplasia epithelial cells under low androgen level via modulation of CCL5/STAT5/CCND1 signaling pathway.

Previous studies by our group have shown that low intra-prostatic dihydrotestosterone (DHT) induced BPH epithelial cells (BECs) to recruit CD8+ T cells. However, the influence of the recruited CD8+ T cells on BECs under a low androgen level is still unknown. Here, we found CD8+ T cells have the capacity to promote proliferation of BECs in low androgen condition. Mechanism dissection revealed that interaction between CD8+ T cells and BECs through secretion of CCL5 might promote the phosphorylation of STAT5 and a higher expression of CCND1 in BECs. Suppressed CCL5/STAT5 signals via CCL5 neutralizing antibody or STAT5 inhibitor Pimozide led to reverse CD8+ T cell-enhanced BECs proliferation. IHC analysis from Finasteride treated patients showed PCNA expression in BECs was highly correlated to the level of CD8+ T cell infiltration and the expression of CCL5. Consequently, our data indicated infiltrating CD8+ T cells could promote the proliferation of BECs in low androgen condition via modulation of CCL5/STAT5/CCND1 signaling. The increased secretion of CCL5 from the CD8+ T cells/BECs interaction might help BECs survive in a low DHT environment. Targeting these signals may provide a new potential therapeutic approach to better treat BPH patients who failed the therapy of 5α-reductase inhibitors.

我们小组先前的研究表明，前列腺内低水平的双氢睾酮（DHT）诱导良性前列腺增生（BPH）上皮细胞（BECs）募集CD8 + T细胞。然而，在低雄激素水平下，募集的CD8 + T细胞对BECs的影响仍然未知。在此，我们发现CD8 + T细胞在低雄激素条件下具有促进BECs增殖的能力。机制剖析显示，CD8 + T细胞与BECs通过分泌CCL5相互作用，可能促进BECs中STAT5的磷酸化以及CCND1的高表达。通过CCL5中和抗体或STAT5抑制剂匹莫齐特抑制CCL5/STAT5信号，可逆转CD8 + T细胞增强的BECs增殖。对非那雄胺治疗患者的免疫组化分析表明，BECs中的PCNA表达与CD8 + T细胞浸润水平以及CCL5的表达高度相关。因此，我们的数据表明，浸润的CD8 + T细胞可通过调节CCL5/STAT5/CCND1信号通路，在低雄激素条件下促进BECs增殖。CD8 + T细胞与BECs相互作用导致的CCL5分泌增加，可能有助于BECs在低DHT环境中存活。针对这些信号可能为更好地治疗5α - 还原酶抑制剂治疗失败的BPH患者提供一种新的潜在治疗方法。