Target-Dependent Expression of IL12 by synNotch Receptor-Engineered NK92 Cells Increases the Antitumor Activities of CAR-T Cells
Target-Dependent Expression of IL12 by synNotch Receptor-Engineered NK92 Cells Increases the Antitumor Activities of CAR-T Cells
复制标题
synNotch 受体工程化 NK92 细胞靶标依赖性表达 IL12 可增强 CAR-T 细胞的抗肿瘤活性
DOI：
10.3389/fonc.2019.01448
复制
发表时间：
2019-12-19
影响因子：
4.7
通讯作者：
Li, Zonghai
中科院分区：
文献类型：
--
作者：
Luo, Hong;Wu, Xiuqi;Li, Zonghai
IL 12是关键免疫细胞（包括T细胞和NK细胞）的免疫刺激细胞因子。然而，全身施用IL 12具有严重的副作用，这限制了其在患者中的临床应用。最近，已经开发了合成的Notch（synNotch）受体，其诱导转录激活并响应于特异性抗原的重组而递送治疗有效载荷。NK 92细胞是一种人类自然杀伤（NK）细胞系，已被开发作为癌症辅助免疫治疗的工具。在这里，我们探索了使用synNotch受体工程改造的NK 92细胞在肿瘤部位选择性分泌IL 12并增加嵌合抗原受体（CAR）修饰的T细胞的抗肿瘤活性的可能性。与另一个调控元件活化T细胞核因子（NFATs）应答启动子相比，synNotch受体更好地控制细胞因子的表达。用GPC 3特异性synNotch受体转导的NK 92细胞可以响应于癌细胞中表达的GPC 3抗原而产生促炎细胞因子IL 12（GPC 3-Syn-IL 12-NK 92）。体内控制IL 12产生的GPC 3-Syn-IL 12-NK 92细胞可以增强GPC 3重定向的CAR T细胞的抗肿瘤能力，并增加T细胞的浸润而不诱导毒性。综上所述，我们的结果表明，通过synNotch工程改造的NK 92细胞补充IL 12可以以靶依赖性方式分泌IL 12，并促进CAR-T细胞的抗肿瘤效率。通过synNotch工程化的NK 92细胞局部表达IL 12可能是增强CAR-T细胞治疗的临床结果的安全方法。
IL12 is an immune-stimulatory cytokine for key immune cells including T cells and NK cells. However, systemic administration of IL12 has serious side effects that limit its clinical application in patients. Recently, synthetic Notch (synNotch) receptors have been developed that induce transcriptional activation and deliver therapeutic payloads in response to the reorganization of specific antigens. NK92 cell is a human natural killer (NK) cell line which has been developed as tools for adjuvant immunotherapy of cancer. Here, we explored the possibility of using synNotch receptor-engineered NK92 cells to selectively secrete IL12 at the tumor site and increase the antitumor activities of chimeric antigen receptor (CAR)-modified T cells. Compared with the nuclear factor of activated T-cells (NFATs) responsive promoter, which is another regulatory element, the synNotch receptor was better at controlling the expression of cytokines. NK92 cells transduced with the GPC3-specific synNotch receptor could produce the proinflammatory cytokine IL12 (GPC3-Syn-IL12-NK92) in response to GPC3 antigen expressed in cancer cells. In vivo GPC3-Syn-IL12-NK92 cells controlling IL12 production could enhance the antitumor ability of GPC3-redirected CAR T cells and increase the infiltration of T cells without inducing toxicity. Taken together, our results demonstrated that IL12 supplementation by synNotch-engineered NK92 cells could secrete IL12 in a target-dependent manner, and promote the antitumor efficiency of CAR-T cells. Local expression of IL12 by synNotch-engineered NK92 cells might be a safe approach to enhance the clinical outcome of CAR-T cell therapy.