Tumour-reactive T cells infiltrating solid tumours are often rendered exhausted, a cell differentiation state characterised by upregulation of inhibitory receptors and reduced effector function. The process of T-cell exhaustion permits cancer progression and interferes with immunotherapy response. Efforts to overcome T-cell exhaustion, such as immune checkpoint blockade (ICB), can lead to remarkable clinical responses in some patients with cancer. However, only a minority of patients respond to ICB, responses often lack durability, and undesirable immune-related toxicities are prevalent. Thus, elucidating additional factors that limit T-cell function in cancer may reveal new therapeutic targets to safely promote tumour eradication. While persistent T-cell receptor (TCR) signalling due to chronic tumour antigen is a major driver of exhaustion, the suppressive tumour microenvironment (TME) also contributes.1 Over the last two decades, the ectoenzymes CD39 and CD73, which degrade extracellular ATP to adenosine, have been implicated in T-cell exhaustion.2 3 In cancer, stressed or damaged cells release ATP. Subsequently, CD39 and CD73 work in concert to convert extracellular ATP to adenosine, which has broad immunosuppressive effects.2 3 In T cells, adenosine regulates proximal TCR signalling events, thereby reducing T-cell effector function. CD39 is highly expressed on exhausted T cells found in human cancers4 5 and cancer or persistent viral infection mouse models.6–8 Here, Potenza et al 9 investigate the phenotypic traits of human T cells infiltrating colorectal cancer (CRC) tumours and metastases. Using transcriptional profiling, flow cytometry and …

中文翻译：

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TCR 工程 T 细胞中 CD39 缺失增强抗肿瘤免疫力

浸润实体瘤的肿瘤反应性 T 细胞通常会被耗尽，这是一种细胞分化状态，其特征是抑制性受体上调和效应器功能降低。 T 细胞耗竭的过程会导致癌症进展并干扰免疫治疗反应。克服 T 细胞耗竭的努力，例如免疫检查点阻断 (ICB)，可以在一些癌症患者中产生显着的临床反应。然而，只有少数患者对ICB有反应，反应往往缺乏持久性，并且不良的免疫相关毒性很普遍。因此，阐明限制癌症中 T 细胞功能的其他因素可能会揭示安全促进肿瘤根除的新治疗靶点。虽然慢性肿瘤抗原导致的持续 T 细胞受体 (TCR) 信号传导是疲劳的主要驱动因素，但抑制性肿瘤微环境 (TME) 也起到了一定作用。1 在过去二十年中，胞外酶 CD39 和 CD73 将细胞外 ATP 降解为腺苷与 T 细胞耗竭有关。2 3 在癌症中，受到压力或受损的细胞会释放 ATP。随后，CD39 和 CD73 协同作用，将细胞外 ATP 转化为腺苷，具有广泛的免疫抑制作用。2 3 在 T 细胞中，腺苷调节近端 TCR 信号传导事件，从而降低 T 细胞效应器功能。 CD39 在人类癌症 4 5 以及癌症或持续性病毒感染小鼠模型中发现的耗竭 T 细胞上高度表达。 6–8 Potenza 等人 9 在此研究了浸润结直肠癌 (CRC) 肿瘤和转移的人类 T 细胞的表型特征。使用转录分析、流式细胞术和……