The immunosuppressive tumor microenvironment represents a key challenge for chimeric antigen receptor (CAR) T cells in solid tumors and includes the production of the inhibitory cytokine transforming growth factor-β (TGF-β), which limits CAR-T-cell persistence and function. Current strategies involving the blockade of TGF-β signaling have little benefit for solid tumor treatment. Here, we demonstrate a novel inverted cytokine receptor (ICR)-modified CAR-T-cell strategy not only TGF-β signal blockade but also antitumor efficacy enhancement. The newly designed T cells carry an ICR construct that fuses the TGF-β receptor II extracellular domain to the interleukin-15 (IL-15) receptor α cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct. In mice with high-TGF-β solid tumors, our signal-inverted CAR/TB15 T cells effectively treat tumors by blocking TGF-β and repurposing IL-15 stimulative signaling, resulting in enhanced CAR-T-cell persistence and function. As a proof of concept, our study results extend synthetic receptor signaling beyond CAR-directed killing, which could endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumors by using a chimeric inverted cytokine receptor.

中文翻译：

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通过反转 TGF-β 信号增强免疫抑制性肿瘤微环境中的 CAR-T 细胞功能。


免疫抑制性肿瘤微环境是实体瘤中嵌合抗原受体 （CAR） T 细胞的关键挑战，包括抑制性细胞因子转化生长因子-β （TGF-β） 的产生，这限制了 CAR-T 细胞的持久性和功能。目前涉及阻断 TGF-β 信号传导的策略对实体瘤治疗几乎没有益处。在这里，我们展示了一种新的反向细胞因子受体 （ICR） 修饰的 CAR-T 细胞策略，不仅可以阻断 TGF β信号，还可以增强抗肿瘤疗效。新设计的 T 细胞携带一个 ICR 构建体，该构建体将 TGF-β 受体 II 胞外结构域融合到白细胞介素 15 （IL-15） 受体α胞质结构域（称为 TB15），并通过 CAR 构建体定向到肿瘤抗原表皮生长因子受体。在患有高 TGF β实体瘤的小鼠中，我们的信号反转 CAR/TB15 T 细胞通过阻断 TGF-β 和再利用 IL-15 刺激信号来有效治疗肿瘤，从而增强 CAR-T 细胞的持久性和功能。作为概念验证，我们的研究结果将合成受体信号传导扩展到 CAR 定向杀伤之外，这可以赋予过继转移的 T 细胞新的功能，通过使用嵌合倒置细胞因子受体来克服治疗实体瘤的主要障碍。