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. Methods: 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. Results: High CD39 expression in both tumor and stromal cells was significantly associated with prolonged PFS (respectively:p= 0.0058 andp= 0.0067), particularly in adenocarcinoma (ADC) patients (respectively:p= 0.01 andp= 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],p= 0.005), while low CD73 expression in stromal cells was linked to increased progression risk (HR: 4.81; 95% CI: [1.61, 14.4],p= 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],p= 0.003). Conclusions: 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：嘌呤能信号通路涉及细胞外ATP（eATP）及其代谢产物、嘌呤能受体和外核苷酸酶，在肿瘤微环境（TME）中发挥关键作用，影响肿瘤进展和抗肿瘤免疫反应。本研究检测了139例手术切除的非小细胞肺癌（NSCLC）患者肿瘤细胞及周围间质中CD39、CD73、P2X4和P2X7的表达情况。方法：研究纳入139例NSCLC患者的组织样本。通过标注肿瘤区域获取1.0 mm组织芯构建组织芯片（TMAs）。对2 µm切片进行CD39、CD73、P2X4和P2X7的免疫组化染色。采用QuPath对数字化TMA切片进行分析，通过半定量H-score评估染色强度。使用R软件进行统计学分析（包括生存分析），评估生物标志物表达对患者预后的影响。结果：肿瘤细胞与间质细胞中CD39的高表达均与更长的无进展生存期（PFS）显著相关（分别为：p=0.0058和p=0.0067），在肺腺癌（ADC）患者中尤为明显（分别为：p=0.01和p=0.023）。在多变量Cox模型中，肿瘤细胞低表达CD73与较长PFS相关（HR：0.47；95% CI：[0.28, 0.8]，p=0.005），而间质细胞低表达CD73则与疾病进展风险升高相关（HR：4.81；95% CI：[1.61, 14.4]，p=0.001）。单变量分析显示P2X7与P2X4均未对PFS产生一致影响；但多变量分析提示P2X4可能在NSCLC预后中发挥作用（HR：0.37；95% CI：[0.19, 0.73]，p=0.003）。结论：这些发现强调了嘌呤能信号通路在NSCLC预后中的重要性，并揭示外核苷酸酶CD39和CD73可作为增强抗肿瘤免疫反应的潜在治疗靶点。
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