IL-18R-dependent and independent pathways account for IL-18-enhanced antitumor ability of CAR-T cells.

IL - 18R 依赖性和非依赖性途径解释了 IL - 18 增强的 CAR - T 细胞的抗肿瘤能力。

• 影响指数: 5.834
• 发表时间: 01 2020
• 来源期刊: FASEB J
• DOI: 10.1096/fj.201901809R
• PMID: 31914650
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 生物
• 作者列表: Huang Y,Li D,Zhang PF,Liu M,Liang X,Yang X,Jiang L,Zhang LF,Zhou WL,Su JH,Gong YL,Gou HF,Wei YQ,Wang W

关键词: CAR‐T; IL‐18; IL‐18 receptor; cancer immunotherapy

Mesh: Animals; Antineoplastic Agents / metabolism; Cell Line; Female; HEK293 Cells; Humans; Immunotherapy, Adoptive / methods; Interleukin-18 / metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Receptors, Antigen, T-Cell / metabolism; Receptors, Interleukin-18 / metabolism; Signal Transduction / physiology; T-Lymphocytes / metabolism; Xenograft Model Antitumor Assays / methods

Abstract

Interleukin-18 (IL-18) has been demonstrated to augment the antitumor capacity of chimeric antigen receptor-T cells (CAR-T) but the underlying mechanisms are largely unknown. Here we explored the effects and mechanisms of exogenous IL-18 on the antitumor response of CAR-T cells. IL-18 boosted the cytotoxicity of human epidermal growth factor receptor-2 (HER2)-specific CAR-T cells ex vivo and enhanced the antitumor efficacy of the CAR-T cells in immunodeficient mice, moreover, IL-18 improved the antitumor capacity of OVA-specific T cells in immunocompetent mice, indicating the universal enhancing function of IL-18 for adoptive cell therapy. To address the roles of IL-18 receptor (IL-18R) in the enhancing function, we evaluated the effects of IL-18R knockout (IL-18R-/-) condition in immunocompetent host and CAR-T cells on the IL-18-enhanced antitumor activities. Interestingly, IL-18 persisted to improve the antitumor ability of IL-18R intact CAR-T cells in IL-18R-/- mice. For IL-18R-/- CAR-T cells, however, IL-18 still holds the enhancing ability to boost the antitumor efficacy in IL-18R-/- mice, albeit the ex vivo tumor-killing ability was lower than that of IL-18R intact CAR-T cells, indicating that IL-18R-independent pathway is involved in the enhancement. Furthermore, tagged IL-18 binded to the membrane of IL-18R-/- splenic and lymph node cells and IL-18R intact and IL-18R-/- CAR-T cells showed distinct transcriptomic profiles when stimulated by IL-18. These data demonstrate that IL-18R-independent pathways contribute to functions of IL-18.

摘要

白细胞介素-18（IL-18）已被证明可增强嵌合抗原受体T细胞（CAR-T）的抗肿瘤能力，但其潜在机制尚不清楚。在这里，我们探讨了外源性IL-18对CAR-T细胞抗肿瘤反应的影响和机制。IL-18增强了人表皮生长因子受体2（HER2）特异性CAR-T细胞的体外细胞毒性，并增强了CAR-T细胞在免疫缺陷小鼠中的抗肿瘤功效，此外,IL-18提高免疫活性小鼠OVA特异性T细胞的抗肿瘤能力，表明IL-18用于过继细胞治疗的普遍增强功能。为了探讨IL-18受体（IL-18R）在增强功能中的作用，我们评估了免疫活性宿主和CAR-T细胞中IL-18R敲除（IL-18R-/-）条件对IL-18增强的抗肿瘤活性的影响。有趣的是,IL-18持续改善IL-18R-/-小鼠中IL-18R完整CAR-T细胞的抗肿瘤能力。对于IL-18R-/-CAR-T细胞，然而,IL-18仍然具有增强IL-18R-/-小鼠抗肿瘤功效的能力，尽管离体肿瘤杀伤能力低于IL-18R完整的CAR-T细胞，表明IL-18R非依赖性途径参与增强。此外，标记的IL-18与IL-18R-/-脾和淋巴结细胞的膜结合，IL-18R完整和IL-18R-/-CAR-T细胞在受到IL-18刺激时显示出不同的转录组学谱。这些数据表明不依赖IL-18R的途径有助于IL-18的功能。