肿瘤细胞治疗研究
英文原题：Enhancing human NK cell antitumor function by knocking out SMAD4 to counteract TGFβ and activin A suppression.
转化生长因子 β（TGF-β）和活化素 A 抑制自然杀伤（NK）细胞的功能和增殖，限制了过继性 NK 细胞治疗的疗效。
转化生长因子 β（TGF-β）和 activin A 会抑制 NK 细胞功能及增殖，限制过继 NK 细胞疗法的疗效。受 SMAD4 单倍剂量不足 NK 细胞对 TGF-β 部分耐受的启发，研究者使用 CRISPR-Cas9 敲除人 NK 细胞中的 SMAD4。研究显示，SMAD4 敲除 NK 细胞可抵抗 TGF-β 和 activin A 的抑制，维持细胞毒性、细胞因子分泌以及由 IL-2/IL-15 驱动的增殖。无论单药使用还是与肿瘤靶向治疗性抗体联用，这些细胞均显示增强的肿瘤穿透能力和肿瘤生长控制作用。值得注意的是，SMAD4 敲除 NK 细胞优于接受 TGF-β 抑制剂处理的对照 NK 细胞，凸显维持 SMAD4 非依赖性 TGF-β 信号的益处。SMAD4 敲除可在多种 NK 细胞平台中赋予 TGF-β 耐受性，包括 CD19-CAR NK 细胞、干细胞来源 NK 细胞和 ADAPT-NK 细胞。这些发现表明，敲除 SMAD4 是增强 NK 细胞抗肿瘤活性的通用且有吸引力的策略，为改进 NK 细胞癌症免疫疗法开辟新途径。
Transforming growth factor beta (TGF ) and activin A suppress natural killer (NK) cell function and proliferation, limiting the efficacy of adoptive NK cell therapies. Inspired by the partial resistance to TGF of NK cells with SMAD4 haploinsufficiency, we used CRISPR-Cas9 for knockout of SMAD4 in human NK cells. Here we show that SMAD4 KO NK cells were resistant to TGF and activin A inhibition, retaining their cytotoxicity, cytokine secretion and interleukin-2/interleukin-15-driven proliferation. They showed enhanced tumor penetration and tumor growth control, both as monotherapy and in combination with tumor-targeted therapeutic antibodies. Notably, SMAD4 KO NK cells outperformed control NK cells treated with a TGF inhibitor, underscoring the benefit of maintaining SMAD4-independent TGF signaling. SMAD4 KO conferred TGF resistance across diverse NK cell platforms, including CD19-CAR NK cells, stem cell-derived NK cells and ADAPT-NK cells. These findings position SMAD4 knockout as a versatile and compelling strategy to enhance NK cell antitumor activity, providing a new avenue for improving NK cell-based cancer immunotherapies.
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