Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia.
Mater Research, University of Queensland, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia.
Leukemia. 2020 Oct;34(10):2708-2721. doi: 10.1038/s41375-020-0811-3. Epub 2020 Apr 8.
A growing body of evidence suggests that macrophage immune checkpoint molecules are potential targets in the era of cancer immunotherapy. Here we showed that extracellular adenosine, an abundant metabolite in the tumor microenvironment, critically impedes the therapeutic efficacy of anti-CD20 monoclonal antibodies (mAbs) against B-cell lymphoma. Using a syngeneic B-cell lymphoma model, we showed that host deficiency of adenosine 2A receptor (A2AR), but not A2BR, remarkably improved lymphoma control by anti-CD20 mAb therapy. Conditional deletion of A2AR in myeloid cells, and to a lesser extent in NK cells, augmented therapeutic efficacy of anti-CD20 mAb. Indeed, adenosine signaling impaired antibody-mediated cellular phagocytosis (ADCP) by macrophages and limited the generation of anti-lymphoma CD8 T cells. Pharmacological inhibition of A2AR overcame the adenosine-mediated negative regulation of ADCP by rituximab in a xeno-transplanted lymphoma model. Moreover, aberrant overexpression of CD39, an apical ecto-enzyme for adenosine generation, showed a negative impact on prognosis in patients with diffuse large B-cell lymphoma, as well as on preclinical efficacy of rituximab. Together, adenosine acts as a "don't eat me signal", and may be a potential target to harness anti-lymphoma immunity.
越来越多的证据表明，巨噬细胞免疫检查点分子是癌症免疫治疗时代的潜在靶点。在这里，我们表明细胞外腺苷是肿瘤微环境中丰富的代谢物，严重阻碍了抗 CD20 单克隆抗体（mAb）治疗 B 细胞淋巴瘤的疗效。我们使用同种异体 B 细胞淋巴瘤模型表明，宿主腺苷 2A 受体（A2AR）缺乏而非 A2BR，显著改善了抗 CD20 mAb 治疗的淋巴瘤控制。髓样细胞（在一定程度上为 NK 细胞）中 A2AR 的条件性缺失增强了抗 CD20 mAb 的治疗效果。事实上，腺苷信号通过巨噬细胞损害了抗体介导的细胞吞噬作用（ADCP），并限制了抗淋巴瘤 CD8 T 细胞的产生。在异种移植淋巴瘤模型中，A2AR 的药理学抑制克服了利妥昔单抗介导的 ADCP 的腺苷介导的负调节。此外，CD39 的异常过表达，一种腺苷产生的顶端外酶，对弥漫性大 B 细胞淋巴瘤患者的预后以及利妥昔单抗的临床前疗效产生负面影响。总之，腺苷充当“不要吃我信号”，可能是利用抗淋巴瘤免疫的潜在靶点。
