Abstract 523: Implications of the A2a receptor (A2aR) on tumor microenvironment in non-small cell lung cancer (NSCLC)
Authors: Viveiros Pedro , Sukhadia Bhoomika , Nunna Pratyusha , Park Keon Woo , Chuang Jeffrey , Zou Lihua , Chae Young Kwang 
Published: August 2019

Abstract
Hypoxia-driven adenosine accumulation in tumor microenvironment is believed to play an important role in tumor evasion of immune response. Adenosine via interaction with its A2a receptor, expressed on immune cells, acts as a negative regulator of cytotoxic T-cell immune activity. Increased A2aR expression was observed in tumor infiltrating lymphocytes in freshly resected NSCLC specimens. Higher expression of A2aR was associated with worse prognostic findings in head and neck squamous cell carcinoma. Conversely, it correlated with favorable clinical outcome in non-metastatic lung adenocarcinoma. It has been hypothesized that A2aR antagonism could lead to enhanced efficacy for immune checkpoint blockade. A2aR antagonists have demonstrated favorable in vitro and ex vivo response in NSCLC and ongoing clinical trials are testing these drugs in conjunction with established immunotherapy. However, little is known about the role of A2aR in NSCLC patients. We investigated how A2aR expression affected tumor immune landscape, PD-L1 expression and clinical outcomes in a large pool of NSCLC patients. Methods: We obtained A2aR expression for NSCLC patients from TCGA; adenocarcinoma (ADC), n=586; squamous cell carcinoma (SCC), n=517. The data was arranged into 4 quartiles according to A2aR expression mRNA-seq z-scores, defining the highest quartile as A2aR-high and the lowest quartile as A2aR-low. We evaluated how A2aR expression correlated with a) immune landscape, b) PD-L1 expression, c) tumor mutational burden (TMB) and neoantigen burden, and d) clinical outcome. Results: In ADC, A2aR-high was significantly associated with lower infiltration of activated CD4 and CD8 T cells when compared with A2aR-low patients (12% vs 48% ; 9% vs 47%, all p&lt;0.001). In SCC, similar results were observed (12% vs 61%; 9% vs 52%, all p&lt;0.001). In addition, higher PD-L1 (CD274) expression was observed in A2aR-high ADC (p&lt;0.05). There was no difference on TMB or neoantigen burden between groups. In ADC, A2aR-high was associated with more favorable overall survival (OS) and progression free survival when compared with A2aR-low (median 71 vs 41 months and 84 vs 27 months, respectively, all p&lt;0.05). An inverse trend was noted in SCC, with A2aR-high patients having significantly shorter OS (median 39 vs 71 months, p&lt;0.05). Conclusion: Higher A2aR expression was associated with lower activated CD4 and CD8 T-cells in NSCLC and higher PD-L1 expression in lung ADC, suggesting a potential target for developing new strategies for immunotherapy in NSCLC.
Citation Format: Pedro Viveiros, Bhoomika Sukhadia, Pratyusha Nunna, Keon Woo Park, Jeffrey Chuang, Lihua Zou, Young Kwang Chae. Implications of the A2a receptor (A2aR) on tumor microenvironment in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 523.