肿瘤细胞治疗研究
英文原题：Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma.
Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma.
我们的结果表明，在实体瘤模型中，放射能够有效增强CAR-NK细胞的抗肿瘤效果。与放疗联合将是一种有吸引力的策略，可提高CAR-NK细胞对实体瘤的治疗效果。
嵌合抗原受体（CAR）-NK细胞疗法在血液系统恶性肿瘤治疗中已显示出显著的临床疗效和安全性。然而，由于敌对的肿瘤微环境（TME），其在实体瘤中的疗效有限。放疗常用于实体瘤，并已被证明可改善TME。因此，与放疗联合可能是提高CAR-NK细胞对实体瘤治疗效果的一种潜在策略。
Glypican-3 (GPC3) 被用作肝细胞癌 (HCC) 的 CAR-NK 细胞靶抗原。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，在体外和荷 HCC 的 NCG 小鼠中评估了照射对 CAR-NK92 细胞抗肿瘤活性的影响。最后，为了证明介导照射对 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测定了一些 NK 细胞活化受体重要配体的表达。
在本研究中，我们开发了CXCR2武装的GPC3靶向CAR-NK92细胞，其对HCC细胞表现出特异性且强效的杀伤活性，并增强了对HCC细胞的迁移能力。用照射预处理HCC细胞增强了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，单次分割中仅高剂量（8 Gy）而非低剂量（2 Gy）照射能够显著增强CXCR2武装CAR-NK92细胞的体内抗HCC活性。8 Gy照射显著上调了HCC细胞上NK细胞活化配体的表达。
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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
