Department of Urology, Aichi Medical University School of Medicine, Nagakute, Japan.
Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute, Japan.
Prostate. 2019 Oct;79(14):1658-1665. doi: 10.1002/pros.23890. Epub 2019 Aug 7.
Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer.
A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them.
There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels.
CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer.
调节性 T 细胞（Tregs）在抑制免疫反应中发挥重要作用，包括抗肿瘤免疫反应。C-C 趋化因子受体 4（CCR4）在效应 Tregs 上高度表达，抗 CCR4 抗体作为一种新型的实体瘤免疫治疗药物备受关注。本研究旨在评估前列腺癌中 CCR4 阳性 Tregs（CCR4+Tregs）的表达，并评估 CCR4 靶向治疗前列腺癌的临床潜力。
分析 15 例根治性前列腺切除术（RP）标本和 60 例前列腺癌患者的活检标本，以评估前列腺癌中 CCR4+Tregs 的浸润情况。在 RP 和活检标本中研究了 CCR4+Tregs 数量与临床参数之间的关系。此外，比较了 12 个月内进展为去势抵抗性前列腺癌（CRPC）的预后不良患者（n=13）和激素敏感性前列腺癌稳定超过 12 个月的预后良好患者（n=47）的活检标本中 Treg、CCR4+Treg 和 T 细胞的总数，以及 CCR4+Treg 与 Treg 和 T 细胞的比值。此外，将活检标本分为低 CCR4+Treg 表达组和高 CCR4+Treg 表达组，并比较两组之间的预后。
RP 标本中，Gleason 评分较高（≥8）者 CCR4+Tregs 的表达高于评分较低（<8）者（P=0.041）。在活检标本中，65.9%的 Treg 阳性表达 CCR4。CCR4+Tregs 的数量与临床分期（P<0.001）和 Gleason 评分（P=0.006）呈正相关。与预后良好组相比，预后不良组 Treg 和 CCR4+Treg 的总数明显增加（P=0.024 和 0.01，分别）。此外，低 CCR4+Treg 表达水平的患者进展为 CRPC 的时间（未达到 vs 27.3 个月；P<0.001）和中位生存时间（未达到 vs 69.0 个月；P=0.014）均显著长于高表达水平的患者。
CCR4+Tregs 高度浸润于有进展为 CRPC 潜在风险的预后不良患者的前列腺组织中。此外，CCR4+Tregs 的浸润程度与前列腺癌的预后相关。
