Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland.
Cancer Immunol Res. 2019 Jun;7(6):939-951. doi: 10.1158/2326-6066.CIR-18-0733. Epub 2019 Apr 24.
The CD28-B7 family of receptor-ligand pairs regulates lymphocyte responses through costimulation and coinhibition. It includes checkpoint inhibitors, such as PD-1, which limit antitumor and antivirus T-cell responses. CD28 homolog (CD28H) and B7H7 have been identified as a receptor-ligand pair in this family, which has costimulatory activity in T cells. Here, we show that CD28H is expressed in primary natural killer (NK) cells and that it is a strong activator of NK cells through selective synergy with receptors NKp46 and 2B4 to induce degranulation, lysis of target cells, and production of proinflammatory cytokines. Expression of B7H7 on target cells enhanced both natural and antibody-dependent cellular cytotoxicity of NK cells. Mutation of tyrosine 192 on the CD28H cytoplasmic tail abolished NK-cell activation through CD28H. As B7H7 is broadly expressed in tumor tissues, we engineered a CD28H chimeric antigen receptor (CD28H-CAR) consisting of full-length CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain. Remarkably, expression of CD28H-CAR in NK cells triggered lysis of B7H7 HLA-E tumor cells by overriding inhibition by the HLA-E receptor NKG2A. The cytoplasmic domains of CD28H and of the ζ chain were both required for this activity. Thus, CD28H is a powerful activation receptor of NK cells that broadens their antitumor activity and holds promise as a component of NK-based CARs for cancer immunotherapy.
CD28-B7 家族的受体-配体对通过共刺激和共抑制调节淋巴细胞反应。它包括检查点抑制剂，如 PD-1，它限制抗肿瘤和抗病毒 T 细胞反应。CD28 同源物 (CD28H) 和 B7H7 已被确定为该家族中的一个受体-配体对，它在 T 细胞中具有共刺激活性。在这里，我们表明 CD28H 在原代自然杀伤 (NK) 细胞中表达，并且通过与受体 NKp46 和 2B4 的选择性协同作用，它是 NK 细胞的强激活剂，可诱导脱颗粒、靶细胞溶解和促炎细胞因子的产生。靶细胞上 B7H7 的表达增强了 NK 细胞的自然和抗体依赖性细胞毒性。CD28H 细胞质尾部上酪氨酸 192 的突变通过 CD28H 消除了 NK 细胞的激活。由于 B7H7 在肿瘤组织中广泛表达，我们构建了一个由全长 CD28H 与 T 细胞受体 ζ 链的细胞质结构域融合而成的 CD28H 嵌合抗原受体 (CD28H-CAR)。值得注意的是，CD28H-CAR 在 NK 细胞中的表达通过克服 HLA-E 受体 NKG2A 的抑制作用触发了 B7H7 HLA-E 肿瘤细胞的溶解。CD28H 和 ζ 链的细胞质结构域都需要这种活性。因此，CD28H 是 NK 细胞的一种强大激活受体，它拓宽了它们的抗肿瘤活性，并有望成为基于 NK 的 CAR 用于癌症免疫治疗的组成部分。
