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Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63 Page 756

Figure 2. Adenosine Biosynthesis in Inflamed Tissues. The accumulation of extracellular ATP, driven by stress-induced conditions,
stimulates extracellular ADO production by the enzymes CD39 and CD73. ADO binds four G protein-coupled receptors, A1, A2A, A2B,
and A3. ADO: Adenosine; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ATP: adenosine triphosphate.

CTLA4 from being recognized, the cytotoxic function of the CD8+ T cells is increased to clear the tumor
cells . However, patients with solid tumors tend to relapse and become resistant to checkpoint therapy.
[113]
Maj et al. discovered that when checkpoint therapy is given, there is an increase in the death of cancer cells
and Tregs. The sudden death of these cells releases a high amount of ATP in the TME, which is then
converted to adenosine by CD39 and CD73. This increase in ADO in the TME counteracts checkpoint
therapy and suppresses the antitumor immune response .
[123]
While an increase in CD73 and CD39 is associated with poor prognosis in patients, increasing A2AR and
A2BR expression also contributes to an increased risk of resistance to checkpoint therapy. It has been found
that having an increase in A2AR in non-small cell lung cancer (NSCLC) or A2BR in triple-negative breast
cancer (TNBC) contributes to poor survival [119,124] . Chalmin et al. showed that the adenosine pathway is
involved in resistance to anti-PD-1 therapies. They demonstrated that when patients were given checkpoint
therapy, there was an increase in CD73, leading to resistance . Combination therapies targeting CD73,
[125]
and checkpoint inhibitors may help overcome early resistance in solid tumors. Studies have shown that
targeting CD73 and PD-1 in murine colon tumors can inhibit tumor growth . The idea that targeting both
[126]
the adenosine pathway and checkpoint inhibitors may overcome resistance in solid tumors gives promise to
advancing immunotherapy.

Endothelial cells increase CD39 and CD73 levels during hypoxia in tumors, leading to angiogenesis
Hypoxia occurs in solid tumors and suppresses immune cell infiltration by activating hypoxia-inducible
factor 1/2 (HIF1/2), IL-6, TGFβ, and TNF. Under these conditions, endothelial, tumor, and various
suppressive immune cells increase CD73 and CD39 to increase ATP conversion to AMP and ADO [39,127] .
Tumor cells that increase CD73 expression can generate ADO to interact with A2ARs on the tumor cells to
stimulate an increase in VEGF secretion . VEGF works to increase angiogenesis within the tumor and
[128]
provides nutrients and oxygen for growth and metastasis [Figure 3].

Endothelial cells express CD39 within tumors to degrade ATP and promote increased neovascularization
and tumor growth . To have the ADO concentration needed to sustain the tumor-protective endothelial
[129]
barrier, CD73 and A2BR are needed within the TME . Feng et al. and Sun et al. demonstrated that
[130]
inhibiting CD39 on solid tumor endothelial cells decreased angiogenesis and tumor growth [129,131] . CD39 on
endothelial cells and the vascular is highly expressed within pancreatic and rectal carcinoma. High