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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 617

[63]
+
activation and IFNg production in CD8 T cells , highlighting the inverse relationship between adenosine
and CD8 T cell function. Adenosine production within the TIME is also regulated by cancer exosomes,
+
which are endosomal-derived extracellular vesicles [64,65] . Specifically, cancer exosomes were found to express
CD39 and CD73, leading to inhibition of T cell activation and proliferation in human neuroblastoma
samples and bladder, colorectal, prostate, and breast cancer cell lines . Accumulation of adenosine
[66]
[67]
within the TIME also severely hinders tumor infiltration by CD8 T cells due to adenosine-mediated
+
dysfunction of KCa3.1 channels [68,69] . KCa3.1 is a potassium channel that regulates Ca influx, which affects
2+
T cell gene expression, activation, and differentiation . Inhibition of KCa3.1 by adenosine reduced T cell
[70]
migration and cytokine production , and decreased KCa3.1 channel activity, but not protein expression,
[69]
resulting in decreased tumor infiltration . Building on this, the same group later found that anti-PD-1
[68]
+
therapy increased the activity of ion channels KCa3.1 and Kv1.3, leading to enhanced CD8 T cell
infiltration in head and neck squamous cell carcinoma (HNSCC) patient samples . While not the focus of
[71]
this section, it is important to mention that Treg-derived adenosine also drives CD8 T cell
+
dysfunction [56,57,72,73] . On the other hand, increased IL-7 signaling in CD8 T cells inhibits FoXO1 activation,
+
which is a transcription factor that controls T cell proliferation, to overcome the suppressive effects of the
adenosine-rich TIME and promote tumor infiltration and expansion . Leveraging these mechanisms
[74]
might be a viable therapeutic strategy to be used in conjunction with current ICB therapies to overcome
resistance.
Adenosine within the TIME engages with the A2A receptor (A2AR) on CD8 T cells to drive adenosinergic
+
[75]
signaling that results in impaired anti-tumor effects . Early studies found that A2AR signaling inhibited T
cell activation and proliferation , and in the context of cancer, many studies have shown that A2AR
[76]
signaling promotes immune evasion and T cell dysfunction. In mouse melanoma and fibrosarcoma models,
pharmacological inhibition or genetic deficiency of A2AR increases CD8 T cell tumor infiltration and IFNg
+
production, and reduces tumor growth [77,78] . Moreover, targeted knockdown or antagonizing A2AR
increases CD8 T cell infiltration and decreases Treg infiltration and tumor volume in mouse models of
[79]
+
[80]
HNSCC . Similarly, administering A2AR agonists during T cell activation impaired cytotoxic function,
although proliferative capacity was maintained, and these effects persisted after A2AR agonists were
[81]
+
removed . These data demonstrate that even if CD8 T cells infiltrate the adenosine-rich TIME,
adenosinergic signaling reduces their effector functions and renders them incapable of eliminating tumor
cells. However, one study showed that complete abrogation of the A2AR gene in CD8 T cells inhibited
+
expansion and effector functions . In this way, it is important to preserve some degree of A2AR signaling
[75]
in CD8 T cells to maintain proper cell function, highlighting that complete deletion of immunosuppressive
+
targets might not produce the most efficacious results.
The studies thus far have demonstrated that tumor-intrinsic adenosine metabolism adversely affects CD8 T
+
cell function; therefore, it is not surprising that these metabolic alterations also contribute to anti-PD-1/
PD-L1 resistance. To date, there are many drugs in the pre-clinical and clinical stages that target CD39,
CD73, and A2AR, either alone or in combination with anti-PD-1/PD-L1 therapies . Because it is not
[82]
feasible to cover all these data, we have chosen to focus on the relevant articles from 2020 until now to
demonstrate that modulating adenosine metabolism helps overcome resistance to ICB therapies. Using
bioinformatics approaches, researchers showed that adenosine signaling gene signatures are inversely
correlated with survival and efficacy of anti-PD-1 treatment across multiple cancer indications . The first-
[83]
in-human study using an A2AR antagonist with anti-PD-L1 treatment improved the probability of
progression-free survival and overall survival, and monotherapy or combination with anti-PD-L1 increased
+
[84]
CD8 T cell infiltration . However, current A2AR antagonists do not perform well in the adenosine-rich
TIME, so multiple groups have developed novel A2AR antagonists to increase effectiveness [85,86] . Both