A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model
A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model
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DOI：
10.7150/jca.43966
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Yu, Jinming
中科院分区：
文献类型：
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作者：
Huang, Jiaqi;Zhang, Di;Yu, Jinming
胞外蓄积的腺苷通过腺苷2A受体(A(2A)R)抑制抗肿瘤免疫。用DZD2269阻断A(2A)R可在体内外抑制腺苷类似物介导的cAMP反应元件结合蛋白的磷酸化。辐射可引起腺苷的释放，并导致肿瘤区域细胞外游离腺苷的迅速增加。DZD2269是一种新的A(2A)R拮抗剂，可在多种同基因小鼠肿瘤模型中诱导不完全抗肿瘤反应。DZD2269与IR联用可产生协同抗癌作用。IR可增加不同亚型T细胞(包括CD4+、CD8+和Foxp3+T细胞)对肿瘤区域的渗透。IR和DZD2269联合使用可改善肿瘤免疫微环境，抑制调节性T(Treg)细胞的渗透，增强肿瘤浸润性淋巴细胞的干扰素-γ表达。这些结果支持使用A(2A)受体拮抗剂DZD2269作为单一治疗或联合治疗IR的治疗策略。
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-gamma 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.