Medical Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Hematology and Oncology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Eur J Immunol. 2018 Dec;48(12):2031-2041. doi: 10.1002/eji.201847688. Epub 2018 Oct 10.
Natural Killer (NK) cell-based immunotherapy is a promising approach to treat hepatocellular carcinoma (HCC). The mechanisms underlying the regulation of NK cell activity are not completely understood. In this research, we identified the expression of taste receptor type 1 member 1 (T1R1) and taste receptor type 1 member 3 (T1R3) in a subset of hepatic NK cells in a mouse HCC model. T1R1 and T1R3 were selectively expressed in CD49a CD49b NK cells in livers with HCC. In the in vitro cytotoxicity assay, amino acids promoted the tumoricidal effect of CD49a CD49b NK cells through increasing the production of perforin, granzyme B and IFN-γ. Furthermore, using a lentivirus to induce the expression of exogenous T1R1 and T1R3 in normal hepatic NK cells, we found that amino acids enhanced NK cell-mediated cytotoxicity on tumor cells through the T1R1/T1R3 receptor, as demonstrated by more tumor cell lysis, up-regulation of perforin and granzyme B in comparison with control NK cells. In addition, amino acids activated Akt and mechanistic target of rapamycin complex 1 (mTORC1) signaling in NK cells through T1R1/T1R3 receptor. T-bet expression in NK cells was also increased by amino acid treatment. Therefore, T1R1/T1R3 receptor promotes the tumoricidal activity of hepatic CD49a CD49b NK cells.
自然杀伤 (NK) 细胞免疫疗法是治疗肝细胞癌 (HCC) 的一种很有前途的方法。NK 细胞活性调节的机制尚不完全清楚。在这项研究中，我们在小鼠 HCC 模型中鉴定了味觉受体型 1 成员 1 (T1R1) 和味觉受体型 1 成员 3 (T1R3) 在肝 NK 细胞亚群中的表达。T1R1 和 T1R3 在 HCC 肝脏中的 CD49a CD49b NK 细胞中选择性表达。在体外细胞毒性测定中，氨基酸通过增加穿孔素、颗粒酶 B 和 IFN-γ 的产生来促进 CD49a CD49b NK 细胞的杀伤作用。此外，通过慢病毒诱导正常肝 NK 细胞中外源 T1R1 和 T1R3 的表达，我们发现氨基酸通过 T1R1/T1R3 受体增强 NK 细胞对肿瘤细胞的介导的细胞毒性，与对照 NK 细胞相比，肿瘤细胞溶解更多，穿孔素和颗粒酶 B 的表达上调。此外，氨基酸通过 T1R1/T1R3 受体激活 NK 细胞中的 Akt 和雷帕霉素靶蛋白复合物 1 (mTORC1) 信号通路。氨基酸处理还增加了 NK 细胞中 T-bet 的表达。因此，T1R1/T1R3 受体促进肝 CD49a CD49b NK 细胞的杀肿瘤活性。
