Kurowski Konrad, Prozmann Sophie Nicole, Cabrita Figueiredo António Eduardo, Heyer Jannis, Kind Felix, Schröder Karl-Moritz, Passlick Bernward, Werner Martin, Bronsert Peter, Schmid Severin
Institute for Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
Core Facility Histopathology and Digital Pathology Freiburg, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
Cancers (Basel). 2025 Mar 28;17(7):1142. doi: 10.3390/cancers17071142.
BACKGROUND/OBJECTIVES: Purinergic signaling, which involves extracellular ATP (eATP), its metabolites, purinergic receptors and ectonucleotidases, plays a pivotal role in the tumor microenvironment (TME), impacting tumor progression and the antineoplastic immune response. In this study, the CD39, CD73, P2X4, and P2X7 expression in NSCLC tumor cells and the surrounding stroma of 139 resected patients was examined.
The study included tissue samples from 139 NSCLC patients. Tissue microarrays (TMAs) were constructed using 1.0 mm cores from annotated tumor regions. Immunohistochemical staining for CD39, CD73, P2X4, and P2X4 was performed on 2 µm sections. TMA slides were digitized and analyzed with QuPath, where staining intensity was evaluated using a semi-quantitative H-score. Statistical analysis, including survival analysis, was performed using R, to assess the impact of biomarker expression on patient outcomes.
High CD39 expression in both tumor and stromal cells was significantly associated with prolonged PFS (respectively: = 0.0058 and = 0.0067), particularly in adenocarcinoma (ADC) patients (respectively: = 0.01 and = 0.023). In the multivariable Cox model, low CD73 expression in tumor cells correlated with longer PFS (HR: 0.47; 95% CI: [0.28, 0.8], = 0.005), while low CD73 expression in stromal cells was linked to increased progression risk (HR: 4.81; 95% CI: [1.61, 14.4], = 0.001). Neither P2X7 nor P2X4 demonstrated a consistent effect on PFS in univariable analyses; however, multivariable analyses suggested that P2X4 might play a prognostic role in NSCLCs (HR: 0.37; 95% CI: [0.19, 0.73], = 0.003).
These findings underscore the importance of purinergic signaling in NSCLC prognosis and highlight the role of the ectonucleotidases CD39 and CD73 as potential therapeutic targets to enhance antineoplastic immune responses.
背景/目的：嘌呤能信号传导涉及细胞外ATP（eATP）、其代谢产物、嘌呤能受体和外核苷酸酶，在肿瘤微环境（TME）中起关键作用，影响肿瘤进展和抗肿瘤免疫反应。在本研究中，检测了139例接受手术切除患者的非小细胞肺癌（NSCLC）肿瘤细胞及周围基质中CD39、CD73、P2X4和P2X7的表达情况。
本研究纳入了139例NSCLC患者的组织样本。使用来自注释肿瘤区域的1.0毫米组织芯构建组织微阵列（TMA）。在2微米切片上对CD39、CD73、P2X4和P2X4进行免疫组织化学染色。TMA载玻片进行数字化处理并使用QuPath进行分析，其中使用半定量H评分评估染色强度。使用R进行包括生存分析在内的统计分析，以评估生物标志物表达对患者预后的影响。
肿瘤细胞和基质细胞中高CD39表达均与无进展生存期（PFS）延长显著相关（分别为：P = 0.0058和P = 0.0067），尤其是在腺癌（ADC）患者中（分别为：P = 0.01和P = 0.023）。在多变量Cox模型中，肿瘤细胞中低CD73表达与较长的PFS相关（风险比：0.47；95%置信区间：[0.28, 0.8]，P = 0.005），而基质细胞中低CD73表达与进展风险增加相关（风险比：4.81；95%置信区间：[1.61, 14.4]，P = 0.001）。在单变量分析中，P2X7和P2X4对PFS均未显示出一致的影响；然而，多变量分析表明P2X4可能在NSCLC中发挥预后作用（风险比：0.37；95%置信区间：[0.19, 0.73]，P = 0.003）。
这些发现强调了嘌呤能信号传导在NSCLC预后中的重要性，并突出了外核苷酸酶CD39和CD73作为增强抗肿瘤免疫反应潜在治疗靶点的作用。
