Metabolic reprogramming by adenosine antagonism and implications in non-small cell lung cancer therapy

ElsevierVolume 32, October 2022, 100824NeoplasiaAbstract

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.

Keywords

Non-small cell lung cancer

Tumor and immune cells

Gene mutation

A2AR/A2BR antagonist

Tumor microenvironment

Metabolism

AbbreviationsNSCLC

non-small cell lung cancer

LUSC

lung squamous cell carcinoma

TME

tumor microenvironment

A2AR

adenosine A2A receptor

A2BR

adenosine A2B receptor

TCGA

the cancer genome atlas

EGFR

epidermal growth factor receptor

STK11

serine/threonine kinase 11

KRAS

Kirsten rat sarcoma viral oncogene homolog

KEAP1

Kelch-like ECH-associated protein 1

mTORC1

Mechanistic target of rapamycin complex 1

ATP

Adenosine triphosphate

CD73

Ecto-5’-nucleotidase which catalyzes the conversion of AMP (adenosine monophosphate) to adenosine

CD39

NTPDase1, ectoenzyme which catalyzes the conversion of ATP to AMP

CD38

NADase, ectoenzyme which catalyzes the conversion of NAD+ to ADP-ribose and cyclic ADP-ribose

AMPK

adenosine monophosphate-activated protein kinase

OCR

oxygen consumption rate

SRC

spare respiratory capacity

p-S6

phosphorylation of ribosomal protein S6

OXPHOS

oxidative phosphorylation

ROS

reactive oxygen species

TCA cycle

tricarboxylic acid cycle

ARE

antioxidant response element

ICIs

immune checkpoint inhibitors

TILs

tumor infiltrating lymphocytes

© 2022 The Authors. Published by Elsevier Inc.

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