Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia.
Cancer Cell. 2016 Sep 12;30(3):391-403. doi: 10.1016/j.ccell.2016.06.025.
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.
针对腺苷能途径的临床前研究因其在克服肿瘤诱导的免疫抑制方面的临床潜力而备受关注。在这里，我们通过使用基因敲除小鼠或针对这些分子的治疗药物，鉴定出共阻断产生腺苷的外核苷酸酶 CD73 和介导白细胞中腺苷信号的 A2A 腺苷受体 (A2AR)，可限制肿瘤的起始、生长和转移。这种肿瘤控制需要效应淋巴细胞和干扰素-γ，而当结合激活的 Fc 受体时，针对 CD73 的抗体则促进体内的最佳治疗反应。在使用完全人源抗 CD73 的双向混合淋巴细胞反应中，我们证明了 Fc 受体结合增强了促炎细胞因子的产生。
