A(2A)R Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

Accumulated extracellular adenosine suppresses antitumor immunity via adenosine 2A receptor (A(2A)R). Blockade of A(2A)R with DZD2269 can inhibit phosphorylation of cAMP response element-binding protein mediated by adenosine analogue in vitro and in vivo. Irradiation can cause the release of adenosine and lead to a rapid increase in free extracellular adenosine in the tumour area. DZD2269, a novel A(2A)R Antagonism, induces incomplete antitumor responses in multiple syngeneic mouse tumour models. Combining DZD2269 with IR can induce a synergistic anticancer effect. IR increases the infiltration of various subtypes of T cells, including CD4+, CD8+ and Foxp3+ T cells, into the tumour area. Combining IR and DZD2269 improves the tumour immune microenvironment, leading to suppressed infiltration of regulatory T (Treg) cells and enhanced IFN-γ expression by tumour-infiltrating lymphocytes. The results support the use of A(2A)R antagonism with DZD2269 as a therapeutic strategy for monotherapy or combination therapy with IR.