State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, P.R. China.
The College of Life Sciences, Sichuan University, Chengdu, P.R. China.
Oncoimmunology. 2022 Sep 22;11(1):2127282. doi: 10.1080/2162402X.2022.2127282. eCollection 2022.
A major challenge in natural killer (NK) cell immunotherapy is the limited persistence of NK cells . However, the proliferation of NK cells is dependent on cytokines such as interleukin-2 (IL-2). Although IL-2 is a critical cytokine for NK cell activation and survival, IL-2 administration in adoptive NK cell therapy can induce adverse toxicities. To improve the persistence of NK cells and attenuate the systemic toxicity of IL-2, we constructed a cell-restricted artificial IL-2, named membrane-bound IL-2 (mbIL-2), comprising human IL-2 and human IL-2Rα joined by a classic linker. We found that mbIL-2-activated NK-92 cells can survive and proliferate and , independent of exogenous IL-2, while mbIL-2-expressing NK-92 cells do not support bystander cell survival or proliferation. Additionally, mbIL-2 enhanced NK-92 cell-mediated antitumor activity by tuning the IL-2 receptor downstream signals and NK cell receptor repertoire expression. To conclude, our novel mbIL-2 improves NK-92 cell persistence and enhances NK-92 cell-mediated antitumor activity. NK-92 cells genetically modified to express the novel mbIL-2 with potential significance for clinical development.
自然杀伤 (NK) 细胞免疫疗法的一个主要挑战是 NK 细胞的持续存在时间有限。然而，NK 细胞的增殖依赖于细胞因子，如白细胞介素-2 (IL-2)。尽管 IL-2 是 NK 细胞激活和存活的关键细胞因子，但在过继性 NK 细胞治疗中给予 IL-2 会引起不良反应毒性。为了提高 NK 细胞的持久性并减轻 IL-2 的全身毒性，我们构建了一种细胞受限的人工 IL-2，称为膜结合 IL-2（mbIL-2），由人 IL-2 和人 IL-2Rα 通过经典接头连接而成。我们发现，mbIL-2 激活的 NK-92 细胞可以在没有外源性 IL-2 的情况下存活和增殖，而表达 mbIL-2 的 NK-92 细胞则不能支持旁观者细胞的存活或增殖。此外，mbIL-2 通过调节 IL-2 受体下游信号和 NK 细胞受体谱表达来增强 NK-92 细胞介导的抗肿瘤活性。总之，我们的新型 mbIL-2 提高了 NK-92 细胞的持久性并增强了 NK-92 细胞介导的抗肿瘤活性。用新型 mbIL-2 基因修饰的 NK-92 细胞具有重要的临床开发潜力。
