<p>Targeting the A₃ adenosine receptor to treat cytokine release syndrome in cancer immunotherapy</p>

Abstract

Cancer patients undergoing immunotherapy may develop cytokine release syndrome (CRS), an inflammatory cytokine storm condition, followed by neurotoxic manifestations and may be life-threatening. The current treatments for CRS successfully reduce the inflammatory response but may limit the anticancer effect of the given immunotherapy and fail to overcome the neurotoxic adverse events. Adenosine, a ubiquitous purine nucleoside, induces a plethora of effects in the body via its binding to four adenosine receptors A 1 , A 2a , A 2b , and the A 3. Highly selective agonists to the A 3 adenosine receptor act as inhibitors of proinflammatory cytokines, possess robust anti-inflammatory and anticancer activity, and concomitantly, induce neuroprotective effects. Piclidenoson and namodenoson belong to this group of compounds, are effective upon oral administration, show an excellent safety profile in human clinical studies, and therefore, may be considered as drug candidates to treat CRS. In this article, the detailed anti-inflammatory characteristics of these compounds and the rationale to use them as drugs to combat CRS are described.

<p>Cytokine Release Syndrome: Current Perspectives</p>

“…A3 adenosine receptors are expressed on various immune cells and activation of A 3 AR has been correlated with anti-inflammation52 Binding of A 3 AR with A 3 AR agonists inhibit inflammatory cytokine production and release by inhibiting the production of inflammatory cytokines through downregulation of NF-κB, hence reducing production of pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 53,54. Highly selective A 3 AR agonists such as namodenoson and piclidenoson could represent potential therapeutic options for CRS treatment, but require additional clinical investigation 53…”

The identification of a potential prognostic model of colon cancer using integrated bioinformatics analysis

“…In this study, the prognostic model was constructed based on the 12-prognostic gene signature (including 12 DEGs, ADORA3, CPA3, CPM, EDN3, FCRL2, MFNG, NAT1, PCSK5, PPARGC1A, PRRX2, TNFRSF17, and WDR78). Speci cally, adenosine receptor A3 (ADORA3) protein encoded by ADORA3 gene is G-proteincoupled receptor that are implicated in in ammatory and immunological responses as well as cancer growth in various diseases through in uencing nucleotide metabolic process (34)(35)(36). Increasing evidence has proved that ADORA3 is overexpressed in several cancers, including breast cancer (37), thyroid cancer (38), bladder cancer (39), and colon cancer (40) and functions as a tumor promoter (41).…”

Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development

“…Secondarily, the trial examined using the A 3 AR as a predictive marker of the CF102 clinical response. The use of A 3 AR to prevent cytokine release syndrome in cancer immunotherapy has been proposed (Cohen and Fishman, 2019).…”