Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
GenomeDx Biosciences Inc., Vancouver, BC, Canada.
J Natl Cancer Inst. 2019 Mar 1;111(3):301-310. doi: 10.1093/jnci/djy141.
Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets.
We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided.
Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03).
In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.
免疫疗法在治疗前列腺癌方面的效果不如其他实体肿瘤。我们试图更好地了解前列腺癌中的免疫景观，并确定免疫相关的生物标志物和潜在的治疗靶点。
我们分析了 7826 例前瞻性收集的前列腺切除术样本（2013-2016 年）和 1567 例具有长期临床结局的回顾性样本的基因表达数据，共 9393 例样本，均在 CLIA 认证实验室的相同商业临床平台上进行了分析。主要结局是远处无转移生存（DMFS）。次要结局包括生化无复发生存（bRFS）、前列腺癌特异性生存（PCSS）和总生存（OS）。所有统计检验均为双侧。
无监督层次聚类的标志性通路显示出与免疫相关的肿瘤聚类。基于文献中免疫特异性基因的估计免疫含量评分增加与 bRFS 较差相关（危险比 [HR] = 1.26 [95%置信区间 [CI] = 1.12 至 1.42]；P < 0.001）、DMFS（HR = 1.34 [95%CI = 1.13 至 1.58]；P < 0.001）、PCSS（HR = 1.53 [95%CI = 1.21 至 1.92]；P < 0.001）和 OS（HR = 1.27 [95%CI = 1.07 至 1.50]；P = 0.006）。Cibersort 的去卷积显示肥大细胞、自然杀伤细胞和树突状细胞可改善 DMFS，而巨噬细胞和 T 细胞则可导致 DMFS 恶化。有趣的是，虽然 PD-L1 没有预后价值，与其在前列腺癌中的低表达一致，但 PD-L2 的表达水平统计学上显著更高（P < 0.001），与 bRFS 较差相关（HR = 1.17 [95%CI = 1.03 至 1.33]；P = 0.01）、DMFS（HR = 1.25 [95%CI = 1.05 至 1.49]；P = 0.01）和 PCSS（HR = 1.45 [95%CI = 1.13 至 1.86]；P = 0.003）。PD-L2 与基因集富集分析中的免疫相关途径强烈相关，这表明它在临床前列腺癌样本中的免疫调节中发挥着重要作用。此外，PD-L2 与放射反应途径相关，并且在多变量交互分析中也预测了对术后放射治疗（PORT）的反应（P = 0.03）。
在迄今为止最大规模的此类研究中，这些结果说明了肿瘤-免疫相互作用、预后和对放射治疗反应之间的复杂关系，并将 PD-L2 作为前列腺癌的潜在新治疗靶点，可能与放射治疗联合使用。
