The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK.
The Institute of Cancer Research, London, UK.
Eur Urol. 2021 Jun;79(6):736-746. doi: 10.1016/j.eururo.2021.01.017. Epub 2021 Mar 5.
CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated.
To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS: RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38 TIIC densities between CSPC and CRPC biopsies were analysed using a negative binomial mixed model. Differences in the proportions of CD38 epithelial cells between non-matched benign prostatic epithelium and PC were compared using Fisher's exact test. Differences in the proportions of biopsies containing CD38 tumour epithelial cells between matched CSPC and CRPC biopsies were compared by McNemar's test. Univariable and multivariable survival analyses were performed using Cox regression models.
CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38 TIIC density increased with progression to CRPC and was independently associated with worse overall survival. Future studies are required to dissect TIIC CD38 function.
CD38 prostate TIICs associate with worse survival and immunosuppressive mechanisms. The role of CD38 in PC progression warrants investigation as insights into its functions may provide rationale for CD38 targeting in lethal PC.
CD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier.
CD38 是一种可药物靶向的细胞外酶，参与腺苷的生成，而后者与肿瘤免疫逃逸有关。其在前列腺肿瘤浸润免疫细胞（TIICs）中的表达和作用尚未阐明。
描述 CD38 在前列腺癌细胞和 TIICs 上的表达，并将其与临床结局相关联。
设计、地点和参与者：对国际癌症抗癌协会/前列腺癌基金会（SU2C/PCF）队列中 159 名转移性去势抵抗性前列腺癌（mCRPC）患者的 RNAseq 进行分析，并对弗雷德·哈钦森癌症研究中心队列中 63 名患者的 171 名 mCRPC 样本进行分析。在 2016 年至 2018 年间获得的 51 例去势抵抗性前列腺癌（CRPC）和匹配的、同一患者的去势敏感性前列腺癌（CSPC）活检中，使用经过验证的测定法对 CD38 表达进行免疫组织化学评分，并与回顾性收集的临床数据相关联。
分析 mCRPC 转录组中 CD38 表达与基因表达特征之间的关联。多色免疫荧光法测定前列腺活检组织中 CD38 的表达。使用负二项式混合模型分析 CSPC 和 CRPC 活检中 CD38 TIIC 密度的差异。使用 Fisher 精确检验比较非匹配良性前列腺上皮组织和前列腺中 CD38 上皮细胞的比例差异。使用 McNemar 检验比较匹配的 CSPC 和 CRPC 活检中含有 CD38 肿瘤上皮细胞的活检比例差异。使用 Cox 回归模型进行单变量和多变量生存分析。
mCRPC 中的 CD38 mRNA 表达与上调的免疫信号通路最显著相关。CD38 mRNA 表达与白细胞介素（IL）-12、IL-23 和 IL-27 信号特征以及免疫抑制性腺苷信号和 T 细胞耗竭特征相关。CD38 蛋白在包括 B 细胞和髓样细胞在内的表型多样的 TIIC 上频繁表达，但在肿瘤上皮细胞上基本不存在。CD38 TIIC 密度随进展为 CRPC 而增加，并与总生存不良独立相关。需要进一步的研究来剖析 TIIC CD38 的功能。
CD38 前列腺 TIIC 与更差的生存和免疫抑制机制相关。CD38 在前列腺癌进展中的作用值得研究，因为对其功能的深入了解可能为治疗致命性前列腺癌提供 CD38 靶向治疗的依据。
CD38 表达在围绕前列腺细胞的白细胞表面。这些细胞可能影响前列腺癌的生长和治疗耐药性。CD38 表达更多的前列腺癌患者更有可能早期死亡。
