Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy.
Cell Rep. 2021 Oct 19;37(3):109871. doi: 10.1016/j.celrep.2021.109871.
Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A and NKG2A cells characterize two distinct "intralineages" of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.
人 Vδ2 细胞是先天样 γδ T 效应细胞，对肿瘤具有强大的免疫监视作用。NKG2A 的组成性表达鉴定了一类对癌症具有固有高反应性的 Vδ2 T 细胞。事实上，NKG2A 和 NKG2A 细胞的转录组谱特征表明，Vδ2 T 淋巴细胞存在两个不同的“内谱系”，它们在发育早期出现，保持其表型，并在成年期具有自我更新能力。NKG2A Vδ2 T 细胞的高反应性被恶性细胞表达的人类白细胞抗原 E (HLA-E) 所表达的抑制性信号所抵消，这是一种肿瘤逃逸机制。然而，无论是掩盖还是敲除 NKG2A，都能恢复 Vδ2 T 细胞发挥最高效应功能的能力，即使是针对 HLA-E 肿瘤也是如此。这在临床上非常重要，因为 NKG2A-HLA-E 检查点在肝细胞癌、神经胶质瘤和非小细胞肺癌中的不同程度参与直接影响患者的总生存期。这些发现为开发联合细胞和免疫抗癌疗法开辟了途径。
