A Self-Activating IL-15 Chimeric Cytokine Receptor to Empower Cancer Immunotherapy.

IF 6.2 Q1 IMMUNOLOGY

ImmunoTargets and Therapy Pub Date : 2024-10-10 eCollection Date: 2024-01-01 DOI:10.2147/ITT.S490498

Sumei Chen, Lingrong Yang, Bing Xia, Haitao Zhu, Zhenghao Piao, Youssef Jounaidi

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引用次数: 0

Abstract

Background: 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.

Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.

Results: 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, TGFβ1 substantially reduced NK92^IL5RB killing, suggesting the need to inhibit TGFβ1 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.

Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.

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增强癌症免疫疗法的自激活 IL-15 嵌合细胞因子受体。

背景增强 NK 细胞的抗肿瘤活性需要持续的细胞因子信号传导。白细胞介素-15（IL-15）是一种强效免疫刺激细胞因子，可用于铠装 CAR-NK 和 CAR-T 细胞免疫疗法。然而，提高 IL-15 表达和抗肿瘤效果的策略可能会引发全身毒性，并有可能促进肿瘤发生和自身免疫性疾病：为了克服这些局限性，我们开发了一种新的平台（IL15RB），将带有 IL-2 信号肽的 IL-15 与其受体 IL2Rβ 连接起来：结果：表达IL15RB（NK92IL15RB）的NK92细胞在没有外源细胞因子的情况下可无限扩增，其抗癌活性明显高于由IL-15、IL-2或表达拴系IL-2刺激的NK-92。NK92IL5RB 对辐照和 IL-4 有抵抗力。然而，TGFβ1大大降低了NK92IL5RB的杀伤力，这表明在IL-15介导的免疫疗法中需要抑制TGFβ1。与IL-2相比，IL15RB诱导的STAT3活化较强，但STAT5和STAT1活化较弱。NK92IL15RB细胞长期暴露于癌细胞会不可逆地减少STAT3和STAT1的活化，这表明了STAT3和STAT1在衰竭中的作用。与 CAR-CD19 结合使用可增强 NK92IL15RB 对白血病的抗肿瘤活性，并增加其 STAT5 激活。NK92IL15RB的抗肿瘤活性在与抗PD1结合后进一步增强：我们的数据表明，IL-15 与其受体 IL2Rβ 的系联增强了 NK 细胞的细胞溶解活性。此外，IL-15 的拴系还能防止任何全身毒性风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ImmunoTargets and Therapy IMMUNOLOGY-

CiteScore

16.50

自引率

0.00%

发文量

审稿时长

16 weeks

期刊介绍： Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.