Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China.
State Key Laboratory of Organ Failure Research, Guangdong Province, Guangzhou, China.
J Transl Med. 2024 Oct 13;22(1):929. doi: 10.1186/s12967-024-05724-4.
BACKGROUND: Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. METHODS: Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. RESULTS: In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. CONCLUSIONS: Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.
背景：嵌合抗原受体（CAR）-NK 细胞疗法在治疗血液恶性肿瘤方面显示出显著的临床疗效和安全性。然而，由于肿瘤微环境（TME）的恶劣，这种疗效在实体瘤中受到限制。放疗常用于治疗实体瘤，并已被证明可改善 TME。因此，联合放疗可能是提高 CAR-NK 细胞治疗实体瘤疗效的一种潜在策略。
方法：糖蛋白 3（GPC3）被用作 CAR-NK 细胞治疗肝细胞癌（HCC）的靶抗原。为了促进向 HCC 的迁移，首先开发了靶向 GPC3 的 CXCR2 武装 CAR-NK92 细胞，并评估了它们对 HCC 细胞的细胞毒性和迁移活性。接下来，在体外和 HCC 荷瘤 NCG 小鼠中评估了照射对 CAR-NK92 细胞抗肿瘤活性的影响。最后，为了证明照射对 CAR-NK 细胞增敏作用的潜在机制，分析了照射诱导的差异基因表达谱，并通过 qRT-PCR 和流式细胞术进一步确定了一些重要的 NK 细胞激活受体配体的表达。
结果：在这项研究中，我们开发了靶向 GPC3 的 CXCR2 武装 CAR-NK92 细胞，该细胞对 HCC 细胞表现出特异性和强大的杀伤活性，并增强了向 HCC 细胞的迁移。预处理 HCC 细胞用照射增强了 CXCR2 武装 CAR-NK92 细胞的体外抗 HCC 效应和迁移活性。我们进一步发现，只有高剂量（8Gy）而不是低剂量（2Gy）单次照射才能显著增强 CXCR2 武装 CAR-NK92 细胞在体内抗 HCC 活性。8Gy 照射显著上调了 HCC 细胞上 NK 细胞激活配体的表达。
结论：我们的研究结果表明，照射可有效增强 CAR-NK 细胞在实体瘤模型中的抗肿瘤作用。联合放疗可能是提高 CAR-NK 细胞治疗实体瘤疗效的一种有吸引力的策略。
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