Non-small cell lung cancer (NSCLC) is a heterogeneous disease with genetic and environmental parameters that influence cell metabolism. Because of the complex interplay of environmental factors within the tumor microenvironment (TME) and the profound impact of these factors on the metabolic activities of tumor and immune cells, there is an emerging interest to advance the understanding of these diverse metabolic phenotypes in the TME. High levels of adenosine are characteristic of the TME, and adenosine can have a significant impact on both tumor cell growth and the immune response. Consistent with this, we showed in NSCLC data from TCGA that high expression of the A2BR leads to worse outcome and that expression of A2BR may be different for different mutation backgrounds. We then investigated the metabolic reprogramming of tumor cells and immune cells (T and dendritic cells) by adenosine. We used A2AR and A2BR antagonism or agonism as well as receptor knockout animals to explore whether these treatments altered specific immune compartments or conferred specific therapeutic vulnerabilities. Using the seahorse assay, we found that an A2BR antagonist modulates oxidative stress homeostasis in NSCLC cell lines. In addition, we found distinct metabolic roles of A2AR and A2BR receptors in T cell activation and dendritic cell maturation. These data suggest potential mechanisms and therapeutic benefits of A2 receptor antagonist therapy in NSCLC.
KeywordsNon-small cell lung cancer
Tumor and immune cells
Gene mutation
A2AR/A2BR antagonist
Tumor microenvironment
Metabolism
AbbreviationsNSCLCnon-small cell lung cancer
LUSClung squamous cell carcinoma
TMEtumor microenvironment
A2ARadenosine A2A receptor
A2BRadenosine A2B receptor
TCGAthe cancer genome atlas
EGFRepidermal growth factor receptor
STK11serine/threonine kinase 11
KRASKirsten rat sarcoma viral oncogene homolog
KEAP1Kelch-like ECH-associated protein 1
mTORC1Mechanistic target of rapamycin complex 1
ATPAdenosine triphosphate
CD73Ecto-5’-nucleotidase which catalyzes the conversion of AMP (adenosine monophosphate) to adenosine
CD39NTPDase1, ectoenzyme which catalyzes the conversion of ATP to AMP
CD38NADase, ectoenzyme which catalyzes the conversion of NAD+ to ADP-ribose and cyclic ADP-ribose
AMPKadenosine monophosphate-activated protein kinase
OCRoxygen consumption rate
SRCspare respiratory capacity
p-S6phosphorylation of ribosomal protein S6
OXPHOSoxidative phosphorylation
ROSreactive oxygen species
TCA cycletricarboxylic acid cycle
AREantioxidant response element
ICIsimmune checkpoint inhibitors
TILstumor infiltrating lymphocytes
© 2022 The Authors. Published by Elsevier Inc.
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