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Page 759 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

The hypoxic response also modulates the immune system, affecting innate and adaptive immunity. Hypoxia
can alter the functions of immune cells such as TAMs, neutrophils, DCs, T cells, and NK cells [18,143] .
Hypoxia-driven changes in the TME, for example, can create an immunosuppressive milieu, impairing the
ability of immune cells to target and eliminate cancer cells . Novel therapeutic strategies targeting hypoxia
[144]
and adenosine signaling pathways, including A2BRs, are currently being investigated to improve the efficacy
of existing cancer treatments and overcome treatment resistance .
[14]

The role of ADO and its receptors blockade to overcome resistance
ADO and its receptors are critical in maintaining immunosuppression in the TME, contributing
significantly to immunotherapy resistance. Several clinical trials are exploring the potential of ADO receptor
blockade as a novel strategy to counteract this resistance.

Several A2AR antagonists are currently being explored in clinical trials [Table 1], and two of the more
advanced therapies are discussed further as part of this review: Corvus Pharmaceutical’s ciforadenant and
AstraZeneca’s AZD4635 .
[145]

In a first-in-human Phase 1 dose-escalation study in patients with advanced refractory cancers
(NCT02655822), ciforadenant (either monotherapy or in combination with atezolizumab) was administered
to 502 patients. Of those, a cohort of 68 renal cell carcinoma (RCC) patients yielded clinical responses,
including partial responses (PR) in 11% of patients treated with a combination of A2AR antagonists and
anti-PD-L1 antibodies, and in 3% of patients treated with A2AR antagonists alone . Further, tumor
[146]
regression was observed in an additional 24% of patients, although the regression was not significant
enough to be classified as PR by RECIST criteria. These findings are noteworthy, especially considering that
the patients involved in the study were not only resistant to PD-1 blockade but were also deemed
untreatable prior to the trial.

According to Michail Sitkovsky , the observed tumor regressions in patients with RCC, who were
[147]
previously untreatable and refractory to PD-1 blockade, likely occurred in patients meeting specific criteria:
their tumors were immunogenic, developed tumor-reactive effector T cells, retained a significant number of
effector cells post-toxic cancer chemotherapies, and were protected by immunosuppressive extracellular
ADO to A2AR signaling. Ciforadenant appears to have facilitated the invasion and tumor-rejecting
functions of T and NK cells in these patients; however, the levels of antitumor immunity in responsive
patients were not high enough to achieve a complete response. The major limitation appears to be the lack
or low numbers of tumor-reactive T and NK cells in refractory patients, either due to the tumor’s poor
immunogenicity or past toxic chemotherapies.

A2AR antagonists are anticipated to be most efficacious in patients with sufficient aggressive,
multifunctional tumor-reactive T cells. Without these cells, it could be expected that A2AR antagonists
would only have antitumor effects when combined with cancer vaccines or T-cell transfers that increase the
number of tumor-reactive T cells. Future treatments combining A2AR antagonism with adoptive cell
transfer (ACT) are promising, especially for refractory patients, as ACT ensures the presence of sufficient
T-cells and NK-cells in patients, enhancing the potential for A2AR antagonism as an immunotherapy.

These antagonists have been able to show, both in vitro and in vivo, that blocking the adenosine pathway at
the A2AR increases cytotoxic T cells within the TME, increases cytokine production, and reverses T cell
inhibition.