NKG2 家族成员已成为肿瘤免疫治疗的有希望的靶点。 CD94 可以与抑制性和激活性 NKG2 蛋白形成二聚体，而靶向 CD94 对抗肿瘤免疫的总体效果和价值尚不清楚。研究表明，肿瘤浸润自然杀伤 (NK) 细胞和 CD8 T 细胞上 CD94 的表达上调，并且与它们的耗竭特性有关。携带肿瘤的 CD94 敲除 (CD94-KO) 小鼠表现出肿瘤生长延迟、肺转移减少和生存时间延长。单细胞RNA-seq揭示了CD94-KO小鼠肿瘤微环境的重塑，免疫抑制细胞减少，抗肿瘤免疫细胞增加。此外，NK细胞和CD8 T细胞在CD94-KO小鼠中变得增殖并具有很强的杀瘤作用，从而有助于CD94缺陷的肿瘤抑制作用。在荷瘤人源化小鼠中单独使用人源化抗 CD94 阻断抗体 (h15C10) 进行治疗，可延缓肿瘤进展，并通过联合治疗提高 PD-L1 阻断的治疗效果。我们的研究表明 CD94 可能作为检查点免疫疗法的候选靶点。版权所有 © 2024。由 Elsevier B.V. 出版。

NKG2 family members have emerged as promising targets in tumor immunotherapy. CD94 can dimerize with both inhibitory and activating NKG2 proteins, while the overall effect and value of targeting CD94 on anti-tumor immunity are unclear. Here, it is shown that the expression of CD94 is upregulated on tumor-infiltrating natural killer (NK) cells and CD8+ T cells, and is related to their exhausted characteristics. Tumor-bearing CD94 knockout (CD94-KO) mice exhibit delayed tumor growth, decreased lung metastases, and prolonged survival. Single cell RNA-seq reveal a remodeled tumor microenvironment in CD94-KO mice, with a reduction in immunosuppressive cells and an increase in anti-tumor immune cells. Moreover, NK cells and CD8+ T cells become proliferative and strongly tumoricidal in CD94-KO mice, thus contributing to the tumor inhibition effect of CD94 deficiency. Treatment with a humanized anti-CD94 blocking antibody (h15C10) alone, in tumor-bearing humanized mouse, delays tumor progression, and improves the therapeutic efficacy of PD-L1 blockade through combination therapy. Our study indicates that CD94 may work as a candidate target in checkpoint immunotherapy.Copyright © 2024. Published by Elsevier B.V.