P1.05-020 Opposing Prognostic Roles of CD73 and A2A Adenosine Receptor in Non-Small-Cell Lung Cancer

Abstract

CD73 (otherwise known as ecto-5’-nucleotidase) is an important molecule in the adenosine pathway because it generates adenosine by enzymatically dephosphorylating extracellular AMP, which results in immunosuppressed niche within the tumor microenvironment. A2A adenosine receptor (A2AR) acts as a predominant receptor for adenosine in immune cells and can also be expressed in lung tumor cells. However, the clinical impact of the adenosine pathway in non-small-cell lung cancer (NSCLC) has yet to be uncovered, although the pathway has been shown to have a pivotal role in the regulation of anti-tumor immunity and is considered as one of the promising future treatment targets. We investigated CD73 and A2AR protein expression profiles using immunohistochemistry in tissue microarrays containing 642 resected NSCLC specimens. The expression levels were assessed using the H-score method that ranged from 0 to 300, and cutoffs were determined using the minimum P-value method for overall survival (OS). The associations between their expression levels and clinicopathological and molecular characteristics as well as patients’ prognoses were retrospectively analyzed. The median age of patients was 68 years old (range, 23–88) and 440 (68.5%) patients were male. 438 (68.2%) patients had smoking history and 420 (65.4%) patients had adenocarcinoma histology. Significantly higher expression of both CD73 and A2AR was observed in female than male, in never smokers than ever smokers, and in adenocarcinomas than squamous cell carcinomas. Among adenocarcinomas, both high CD73 and A2AR expression were significantly associated with TTF-1 positivity and EGFR mutations. ALK-positive adenocarcinomas showed significantly higher expression levels of CD73 than ALK-negative tumors. High CD73 expression was an independent indicator of a poor prognosis for NSCLC patients in multivariate Cox regression analyses for OS (hazard ratio (HR), 2.19; 95% confidence interval (CI), 1.38–3.47) and disease-specific survival (DSS) (HR, 2.97; 95% CI, 1.78–4.95). Contrary, high A2AR expression was an independent favorable predictor of prognosis for OS (HR, 0.69; 95% CI, 0.49–0.97) and DSS (HR, 0.51; 95% CI, 0.33–0.79). Among adenocarcinomas, high CD73 expression was an independent poor prognostic marker for OS (HR, 2.73; 95% CI, 1.61–4.63) and DSS (HR, 4.57; 95% CI, 2.54–8.23), whereas high A2AR expression was an independent favorable prognostic marker for DSS (HR, 0.56; 95% CI, 0.32–0.98). Both CD73 and A2AR expression was associated with TTF-1-positive and EGFR-mutant adenocarcinoma. Nonetheless, they had opposing prognostic significance in resected NSCLC.