State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Renji Hosptial, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Immunol. 2019 Jul 19;10:1691. doi: 10.3389/fimmu.2019.01691. eCollection 2019.
Incorporation of inverted cytokine receptor (ICR) such as interleukin (IL)-4 vs. IL-7 (4/7) ICR is one strategy to improve the antitumor activities of chimeric antigen receptor (CAR) modified T (CAR-T) cells facing immunosuppressive cytokines. Here we report a novel interleukin (IL)-4 vs. IL-21 ICR (4/21 ICR) that enhanced CAR-T cell potency in IL-4 tumor milieu via a different working-mechanism from 4/7 ICR. Upon IL-4 stimulation, 4/21 ICR activated the STAT3 pathway and promoted Th17-like polarization and tumor-targeted cytotoxicity in CAR-T cells . Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4 tumors . Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.
掺入反向细胞因子受体（ICR），如白细胞介素（IL）-4 与 IL-7（4/7 ICR），是提高嵌合抗原受体（CAR）修饰 T 细胞（CAR-T）在面对免疫抑制细胞因子时抗肿瘤活性的一种策略。在这里，我们报告了一种新型白细胞介素（IL）-4 与 IL-21 ICR（4/21 ICR），它通过与 4/7 ICR 不同的工作机制，在 IL-4 肿瘤微环境中增强了 CAR-T 细胞的效力。在 IL-4 刺激下，4/21 ICR 激活 STAT3 通路，并促进 CAR-T 细胞中 Th17 样极化和肿瘤靶向细胞毒性。此外，4/21 ICR-CAR T 细胞持续存在并根除了已建立的 IL-4 肿瘤。因此，4/21 ICR 是一种有前途的临床 CAR-T 细胞治疗实体肿瘤的方法，这些肿瘤富含 IL-4。
