Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer.

Yusuke Inoue,Akikazu Kawase,Nobuya Kurabe,Naoki Inui,Kazuya Shinmura,Tomoaki Kahyo,Hiroshi Ogawa,Takafumi Suda,Hiroshi Niwa,Kazuhito Funai,Masayuki Tanahashi,Haruhiko Sugimura,Katsuhiro Yoshimura

doi:10.18632/oncotarget.14434

Abstract

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.

Highlights

Despite significant advances in diagnosis, treatment, and care, the prognosis of non-small-cell lung cancer (NSCLC) has not improved satisfactorily
A2A adenosine receptor (A2AR) expression was significantly lower in tumors with high immune infiltration (N = 73, 11.4%) than in those with low immune infiltration (N = 569, 88.6%, P = 0.0052), whereas there was no significant difference in CD73 expression according to the intensity of immune cell infiltration (Supplementary Figure 1A)
Given the widespread use of immune checkpoint inhibitors in patients with NSCLC, increasing attention has been paid to other molecules that might be involved in tumor immunoescape

Summary

Introduction

Despite significant advances in diagnosis, treatment, and care, the prognosis of non-small-cell lung cancer (NSCLC) has not improved satisfactorily. Further improvements in prognosis are needed even among patients who undergo surgical treatment as local recurrences and distant metastases occur frequently. New predictors of the outcomes of NSCLC are required to improve cancer management. The clinical applications of immune checkpoint inhibitors such as antibodies against www.impactjournals.com/oncotarget programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA4) have yielded significant antitumor activity and some durable responses in several malignancies, including NSCLC [1,2,3,4,5]. Only a limited subset of patients with NSCLC received benefits from such therapy, and more effective treatment strategies such as combinational immunotherapy are needed to improve outcomes to the extent observed in melanoma patients [5]

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Results

Conclusion