Inoue Yusuke, Yoshimura Katsuhiro, Kurabe Nobuya, Kahyo Tomoaki, Kawase Akikazu, Tanahashi Masayuki, Ogawa Hiroshi, Inui Naoki, Funai Kazuhito, Shinmura Kazuya, Niwa Hiroshi, Suda Takafumi, Sugimura Haruhiko
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Oncotarget. 2017 Jan 31;8(5):8738-8751. doi: 10.18632/oncotarget.14434.
In immune cells, CD73 dephosphorylates and converts extracellular AMP into adenosine, which binds the A2A adenosine receptor (A2AR). Blockade of this interaction, which induces an immunosuppressed niche in the tumor microenvironment, represents a potential novel treatment strategy. The clinical significance of CD73 and A2AR expression in non-small-cell lung cancer (NSCLC), however, has yet to be thoroughly investigated. Here we evaluated CD73 and A2AR protein expression levels using immunohistochemistry in tissue microarrays containing 642 resected NSCLC specimens. Furthermore, we compared the expression profiles of 133 paired primary tumors and lymph node metastases. CD73 and A2AR expression levels were significantly higher in females than in males, in never smokers than in ever smokers, and in adenocarcinomas than in squamous cell carcinomas. Among adenocarcinomas, significantly higher CD73 and A2AR expression was observed in TTF-1-positive and mutant EGFR-positive tumors than in their counterparts. Compared with CD73, A2AR expression was more inconsistent between primary tumors and lymph node metastases. Among NSCLC patients, high CD73 expression was an independent indicator of poor prognosis in multivariate Cox regression analyses for overall survival [hazard ratio (HR), 2.18; 95% confidence interval (CI), 1.38-3.46] and recurrence-free survival (HR, 2.05; 95% CI, 1.42-2.95). In contrast, high A2AR expression was an independent predictor of favorable prognosis for overall survival (HR, 0.70; 95% CI, 0.50-0.98) and recurrence-free survival (HR, 0.74; 95% CI, 0.56-0.97). Together, these findings indicate that CD73 and A2AR have opposing prognostic effects, although cases involving CD73 or A2AR expression share some clinicopathological features.
在免疫细胞中，CD73使细胞外的AMP去磷酸化并将其转化为腺苷，腺苷与A2A腺苷受体（A2AR）结合。阻断这种相互作用可在肿瘤微环境中诱导免疫抑制微环境，这代表了一种潜在的新型治疗策略。然而，CD73和A2AR表达在非小细胞肺癌（NSCLC）中的临床意义尚未得到充分研究。在此，我们使用免疫组织化学方法评估了包含642例切除的NSCLC标本的组织微阵列中CD73和A2AR蛋白表达水平。此外，我们比较了133对原发性肿瘤和淋巴结转移灶的表达谱。CD73和A2AR表达水平在女性中显著高于男性，在从不吸烟者中高于曾经吸烟者，在腺癌中高于鳞状细胞癌。在腺癌中，TTF-1阳性和EGFR突变阳性肿瘤中的CD73和A2AR表达显著高于其对应肿瘤。与CD73相比，原发性肿瘤和淋巴结转移灶之间A2AR的表达更不一致。在NSCLC患者中，在多变量Cox回归分析中，高CD73表达是总生存期[风险比（HR），2.18；95%置信区间（CI），1.38 - 3.46]和无复发生存期（HR，2.05；95% CI，1.42 - 2.95）预后不良的独立指标。相反，高A2AR表达是总生存期（HR，0.70；95% CI，0.50 - 0.98）和无复发生存期（HR，0.74；95% CI，0.56 - 0.97）预后良好的独立预测指标。总之，这些发现表明，尽管涉及CD73或A2AR表达的病例具有一些临床病理特征，但CD73和A2AR具有相反的预后影响。
