In recent years, monoclonal antibodies (mAbs) able to reinvigorate antitumor T-cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is attributable to inadequate T-cell priming. For full T-cell activation, 2 signals must be received, and ligands providing the second of these signals, termed costimulation, are often lacking in tumors. Members of the TNF receptor superfamily (TNFRSF) are key costimulators of T cells during infection, and there has been an increasing interest in harnessing these receptors to augment tumor immunity. We here review the immunobiology of 2 particularly promising TNFRSF target receptors, CD27 and OX40, and their respective ligands, CD70 and OX40L, focusing on their role within a tumor setting. We describe the influence of CD27 and OX40 on human T cells based on in vitro studies and on the phenotypes of several recently described individuals exhibiting natural deficiencies in CD27/CD70 and OX40. Finally, we review key literature describing progress in elucidating the efficacy and mode of action of OX40- and CD27-targeting mAbs in preclinical models and provide an overview of current clinical trials targeting these promising receptor/ligand pairings in cancer.

中文翻译：

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CD27 和 OX40 的免疫生物学及其作为癌症免疫治疗靶点的潜力


近年来，能够重振抗肿瘤 T 细胞免疫的单克隆抗体 (mAb) 预示着癌症治疗范式的转变。这些单克隆抗体中最引人注目的是阻断抑制性检查点受体 PD-1 和 CTLA-4，并提高了多种肿瘤类型患者的预期寿命。然而，越来越清楚的是，一些患者对检查点抑制反应失败的原因是 T 细胞启动不足。为了完全激活 T 细胞，必须接收 2 个信号，而肿瘤中通常缺乏提供第二个信号（称为共刺激）的配体。 TNF 受体超家族 (TNFRSF) 的成员是感染过程中 T 细胞的关键共刺激因子，人们越来越关注利用这些受体来增强肿瘤免疫。我们在这里回顾了 2 个特别有前途的 TNFRSF 靶受体 CD27 和 OX40 及其各自的配体 CD70 和 OX40L 的免疫生物学，重点关注它们在肿瘤环境中的作用。我们根据体外研究以及最近描述的几个表现出 CD27/CD70 和 OX40 天然缺陷的个体的表型，描述了 CD27 和 OX40 对人类 T 细胞的影响。最后，我们回顾了关键文献，描述了阐明 OX40 和 CD27 靶向单克隆抗体在临床前模型中的功效和作用模式的进展，并概述了当前针对这些有希望的癌症受体/配体配对的临床试验。