Haymaker Cara, Yang Yi, Wang Junmei, Zou Qiang, Sahoo Anupama, Alekseev Andrei, Singh Divyendu, Ritthipichai Krit, Hailemichael Yared, Hoang Oanh N, Qin Hong, Schluns Kimberly S, Wang Tiejun, Overwijk Willem W, Sun Shao-Cong, Bernatchez Chantale, Kwak Larry W, Neelapu Sattva S, Nurieva Roza
Department of Melanoma Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Department of Immunology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Nat Commun. 2017 Aug 10;8(1):239. doi: 10.1038/s41467-017-00252-w.
T-cell tolerance is a major obstacle to successful cancer immunotherapy; thus, developing strategies to break immune tolerance is a high priority. Here we show that expression of the E3 ubiquitin ligase Grail is upregulated in CD8 T cells that have infiltrated into transplanted lymphoma tumours, and Grail deficiency confers long-term tumour control. Importantly, therapeutic transfer of Grail-deficient CD8 T cells is sufficient to repress established tumours. Mechanistically, loss of Grail enhances anti-tumour reactivity and functionality of CD8 T cells. In addition, Grail-deficient CD8 T cells have increased IL-21 receptor (IL-21R) expression and hyperresponsiveness to IL-21 signalling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8 T cells isolated from lymphoma patients express higher levels of Grail and lower levels of IL-21R, compared with CD8 T cells from normal donors. Our data demonstrate that Grail is a crucial factor controlling CD8 T-cell function and is a potential target to improve cytotoxic T-cell activity.Grail is an E3 ubiquitin ligase that inhibits T-cell receptor signalling in CD4 T cells. Here the authors show Grail also limits IL-21 receptor expression and function in CD8 T cells, is overactive in these cells in patients with lymphoma, and promotes tumour development in a lymphoma transplant mouse model.
T细胞耐受性是癌症免疫治疗成功的主要障碍；因此，制定打破免疫耐受性的策略是当务之急。我们在此表明，E3泛素连接酶Grail在浸润到移植性淋巴瘤肿瘤中的CD8 T细胞中表达上调，而Grail缺陷可实现长期肿瘤控制。重要的是，Grail缺陷的CD8 T细胞的治疗性转移足以抑制已形成的肿瘤。从机制上讲，Grail的缺失增强了CD8 T细胞的抗肿瘤反应性和功能。此外，Grail缺陷的CD8 T细胞中白细胞介素-21受体（IL-21R）表达增加，且对IL-21信号反应增强，因为Grail促进IL-21R的泛素化和降解。此外，与正常供体的CD8 T细胞相比，从淋巴瘤患者分离出的CD8 T细胞表达更高水平的Grail和更低水平的IL-21R。我们的数据表明，Grail是控制CD8 T细胞功能的关键因素，也是改善细胞毒性T细胞活性的潜在靶点。Grail是一种E3泛素连接酶，可抑制CD4 T细胞中的T细胞受体信号传导。本文作者表明，Grail还限制CD8 T细胞中IL-21受体的表达和功能，在淋巴瘤患者的这些细胞中过度活跃，并在淋巴瘤移植小鼠模型中促进肿瘤发展。
