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Page 755 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

tumors and metastatic sites but not in the periphery . The level of CD39 and CD103 double positive (DP)
[109]
cells determines how well patients will respond to immunotherapy [110,111] . However, tumors can still escape
these DP TILs through exhaustion mechanisms. All DP TILs express high levels of PD-1 and other
exhaustion markers . Checkpoint inhibitors may be useful, but there are also additional ADO pathways
[112]
linked to CD39+ cells. Blocking the ADO pathway and using immune checkpoint inhibitors may help keep
the DP CD8+ T cells active and prevent tumor growth.

Tumor cells increase their expression of CD39 to suppress both CD4+ and CD8+ T cell proliferation and
cytotoxicity in the TME . Activation of A2AR in T cells causes increased CD4+ differentiation into Treg
[100]
cells. There is also an increase in additional suppressive receptors such as PD-1, LAG-3, CTLA4, and T cell
immunoglobulin and mucin domain-containing protein 3 (TIM3) on the T cells. Increases in ADO may
have a negative effect on immunotherapies when checkpoint inhibitors are given to patients alone .
[113]
The importance of ADO biosynthesis in the TME
Extracellular ADO is found at low levels in unstressed tissues . It is produced in response to the
[114]
breakdown of adenine nucleotides and AMP outside injured cells [Figure 2] . In response to cancer
[115]
initiation, ADO levels rapidly increase within tissues due to hypoxic, inflammatory, and/or ischemic
conditions. Stressed cells release ATP into the extracellular space as a distress signal that transiently signals
via P2 purinergic receptors. Ectoenzymes CD39 and CD73 can rapidly break down extracellular ATP on cell
surfaces to produce extracellular ADO [116,117] . Initially, CD39 converts ATP into adenosine diphosphate
(ADP) and AMP, followed by CD73-mediated conversion of AMP into ADO . The accumulation of ADO
[118]
in the TME helps create the suppressive niche.

Inhibition of critical immune mechanisms stimulates the formation of the pro-adenosine niche and fibrotic
remodeling
The formation of solid tumors in tissues begins with an increase in cell death, inflammation, and hypoxia.
This leads to an increase in extracellular ATP and ADO within the TME. When the proinflammatory
metabolite extracellular ATP is cleaved into extracellular ADO and is recognized by the A2AR and A2BR
within tumors, there is suppression of immune functions . Endothelial cells within the forming tumor and
[59]
infiltrating immune cells express CD39 and CD73 on their surface. This allows for an increase in ADO
within the TME. Endothelial and immune cells also express A2BR on their surface, and when activated by
ADO, the tumor can suppress immune cell infiltration. Solid tumors become hypoxic, which feeds back to
increase ATP, CD73, and CD39 in the TME to further suppress the immune infiltration . Tumor cells
[115]
interact with suppressive immune cells to increase A2BR expression, leading to metastasis, proliferation,
and VEGF production .
[119]

CAF increases within solid tumors, forming a dense tumor stroma. These CAFs express high levels of CD39
and CD73 on their surface in various solid tumors such as ovarian, pancreatic, colorectal, and breast cancer,
which contribute to ADO production [120-122] . A dense fibrotic stroma allows ADO to remain in high
concentration to drive immunosuppressive signaling throughout the tumor. An increase in A2BR on CAFs
increases the secretion of IL-6 into the TME, which can convert epithelial cells to a more mesenchymal
phenotype . This remodeling of the TME leads to increased metastasis and therapy resistance.
[63]

Increases in the ADO pathway cause resistance to immune checkpoint inhibitor therapies
Immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 have shown great promise for improving
the survival of patients with solid tumors. This form of therapy targets PD-1 and CTLA4 on CD8+ T cells.
Tumor cells inhibit CD8+ T cell function by targeting these checkpoint molecules. By blocking PD-1 and