肿瘤细胞治疗研究
英文原题：A Self-Activating IL-15 Chimeric Cytokine Receptor to Empower Cancer Immunotherapy.
A Self-Activating IL-15 Chimeric Cytokine Receptor to Empower Cancer Immunotherapy.
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我们的数据表明，将 IL-15 与其受体 IL2R 连接可增强 NK 细胞的细胞溶解活性。
增强 NK 细胞抗肿瘤活性需要持续的细胞因子信号。白细胞介素 15（IL-15）是一种强效免疫刺激性细胞因子，用于增强 CAR-NK 和 CAR-T 细胞免疫疗法。然而，提高 IL-15 表达和抗肿瘤作用的策略可能引发全身毒性，并有潜在促进致癌和自身免疫性疾病的风险。
为克服这些局限，我们开发了一种新平台（IL15RB），将带 IL-2 信号肽的 IL-15 锚定于其受体 IL2R。
表达 IL15RB 的 NK92（NK92 IL15RB）细胞无需外源细胞因子即可无限扩增，其抗癌活性显著高于经 IL-15、IL-2 刺激或表达锚定 IL-2 的 NK-92。NK92 IL15RB 对照射和 IL-4 具有抵抗力。然而，TGF-β1 显著降低 NK92 IL15RB 的杀伤能力，提示 IL-15 介导的免疫疗法可能需要抑制 TGF-β1。与 IL-2 相比，IL15RB 强烈激活 STAT3，但对 STAT5 和 STAT1 的激活较弱。NK92 IL15RB 细胞长期暴露于癌细胞后，STAT3 和 STAT1 激活不可逆地降低，提示其可能参与耗竭。联合 CAR-CD19 可增强 NK92 IL15RB 对白血病的抗肿瘤活性并提高 STAT5 激活；再联合抗 PD-1 可进一步增强 NK92 IL15RB 的抗肿瘤活性。
我们的数据提示，将 IL-15 锚定于其受体 IL2R 可增强 NK 细胞的细胞溶解活性；此外，锚定 IL-15 可避免全身毒性风险。
Enhancing NK cells' antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.
To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2R .
NK92-expressing IL15RB (NK92 IL15RB ) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92 IL5RB showed resistance to irradiation and IL-4. However, TGF 1 substantially reduced NK92 IL5RB killing, suggesting the need to inhibit TGF 1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92 IL15RB cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92 IL15RB antitumor activity against leukemia and increased its STAT5 activation. NK92 IL15RB anti-tumors activity was further enhanced by combination with anti-PD1.
Our data suggest that the tethering of IL-15 to its receptor IL2R empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.
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