Abstract 1667: A pilot study correlating baseline plasma levels of adenosine 2A receptor (A2aR) with acute phase reactants in advanced non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors
Authors: McCallen Justin D. , Naqash Abdul R. , Marie Mona A. , Sharma Nitika , Muzaffar Mahvish , Walker Paul R. , Yang Li 
Published: July 2021

Abstract
Background: Acute-phase reactants, such as C-reactive protein (CRP) and IL-6, can modulate immune suppression within the tumor microenvironment (TME) and thus potentially result in inferior outcomes to immune checkpoint inhibitors (ICIs). Immunosuppression within the TME is also be mediated by tumoral adenosine production, via hypoxia-induced exonuclease activity of CD39 and CD73 and adenosine 2a receptor (A2aR) signaling. We sought to evaluate whether plasma levels of A2aR correlate with the acute phase reactants (CRP and IL-6) in advanced NSCLC patients treated with ICIs.
Methods: Between December 2016 and April 2019, we enrolled 18 patients with advanced NSCLC treated with single-agent ICIs or in combination with chemotherapy. We isolated plasma samples from patients before ICI initiation and again after each treatment. Plasma concentrations of A2aR and IL-6 were measured using ELISA. The baseline level of CRP was obtained from peripheral blood at ICI initiation (± 3 days). Previous studies correlating CRP and cancer outcomes defined a C-reactive protein (CRP) cutoff of 10 mg/L to define normal (CRP-N) and high CRP (CRP-H) levels. We assessed the relationship between CRP, IL-6, and A2aR plasma levels. Statistical analyses were performed using the Mann-Whitney test and linear regression analysis.
Results: At the initiation of ICI, the median age of the cohort was 63. Two patients had stage III disease and 16 patients had stage IV disease. Four had squamous cell carcinoma, and 14 had non-squamous cell carcinoma. Six patients were treated with concomitant chemotherapy (pembrolizumab with carboplatin and pemetrexed). Patients received a median of 4 ICI cycles (range: 1-8 cycles) in our study. In the cohort, the median baseline levels of CRP, IL-6, and A2aR were 16.9 mg/L, 5.1 pg/mL, and 3.6 ng/mL, respectively. A positive correlation was present between baseline CRP levels and IL-6 plasma levels (R=0.76; p=0.003). Seven patients were CRP-N, and 11 patients were CRP-H. CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs. 1.3 ng/mL; p=0.01). Likewise, patients with baseline IL-6 levels greater than 5 pg/mL had a higher median baseline level of A2aR (6.0 ng/mL vs. 1.3 ng/mL; p=0.02).
Conclusions: In a small, heterogeneous cohort of advanced NSCLC patients treated with ICIs, we demonstrate that elevated baseline levels of acute-phase reactants (CRP and IL-6) potentially act as an indirect surrogate for high plasma A2aR levels. Validation from larger studies is required to understand the biomarker implications of these findings in determining outcomes to ICIs.
J.D.M. and A.R.N contributed equally to this work.
Citation Format: Justin D. McCallen, Abdul R. Naqash, Mona A. Marie, Nitika Sharma, Mahvish Muzaffar, Paul R. Walker, Li Yang. A pilot study correlating baseline plasma levels of adenosine 2A receptor (A2aR) with acute phase reactants in advanced non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1667.