CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
共表达 CXCR5 和 IL-7 增强 CAR-T 细胞对骨肉瘤有效性的新型策略
英文原题：A novel strategy of co-expressing CXCR5 and IL-7 enhances CAR-T cell effectiveness in osteosarcoma.
查看英文原题
A novel strategy of co-expressing CXCR5 and IL-7 enhances CAR-T cell effectiveness in osteosarcoma.
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研究概要
这些发现凸显了 CXCR5 与 IL-7 共表达提升 CAR-T 细胞疗法抗骨肉瘤疗效的潜力。
中文摘要
背景
实体瘤血供不足、基质结构复杂且环境具有免疫抑制性，这些因素会抑制 CAR-T 细胞进入肿瘤并在其中存活。既往曾利用 CXCR5 增加 CAR-T 细胞浸润 CXCL13+ 肿瘤。另一方面，IL-7 可改善实体瘤环境中 T 细胞的生存和持久性。
方法
我们构建一种新型 NKG2D CAR（C5/IL7-CAR），使其共表达 CXCR5 和 IL-7。人骨肉瘤细胞系 U-2 OS、143B 和 Mg63 均高表达 MICA/B 和 CXCL13，因此适用于本研究。
结果
与传统 CAR 相比，新型 CAR-T 细胞激活、脱颗粒和细胞因子释放能力更强，因而可裂解更多靶细胞。此外，共表达 CXCR5 和 IL-7 降低 PD-1、TIM-3 和 TIGIT 表达，并增加 Bcl-2 表达。新型 CAR-T 细胞增殖增强，并更倾向分化为干细胞记忆 T 细胞表型。C5/IL7-CAR-T 细胞在小鼠模型中清除骨肉瘤的效果优于传统 CAR-T，且小鼠生存更长。与传统 CAR-T 相比，共表达 CXCR5 和 IL-7 还增加植入肿瘤组织中的 CAR-T 细胞数量、细胞因子释放及存活。机制上，C5/IL7-CAR-T 细胞表现出增强的 STAT5 信号。
结论
这些发现凸显共表达 CXCR5 和 IL-7 提高 CAR-T 细胞治疗骨肉瘤疗效的潜力。
展开英文摘要原文
BACKGROUND
Solid tumors are characterized by a low blood supply, complex stromal architecture, and immunosuppressive milieu, which inhibit CAR-T cell entry and survival. CXCR5 has previously been employed to increase CAR-T cell infiltration into CXCL13+ cancers. On the other hand, IL-7 improves the survival and persistence of T cells inside a solid tumor milieu.
METHODS
We constructed a novel NKG2D-based CAR (C5/IL7-CAR) that co-expressed CXCR5 and IL-7. The human osteosarcoma cell lines U-2 OS, 143B, and Mg63 highly expressed MICA/B and CXCL13, thus presenting a perfect avenue for the present study.
RESULTS
Novel CAR-T cells are superior in their activation, degranulation, and cytokine release competence, hence lysing more target cells than conventional CAR. Furthermore, CXCR5 and IL-7 co-expression decreased the expression of PD-1, TIM-3, and TIGIT and increased Bcl-2 expression. Novel CAR-T cells show enhanced proliferation and differentiation towards the stem cell memory T cell phenotype. C5/IL7-CAR-T cells outperformed conventional CAR-T in eradicating osteosarcoma in mouse models and displayed better survival. Additionally, CXCR5 and IL-7 co-expression enhanced CAR-T cell numbers, cytokine release, and survival in implanted tumor tissues compared to conventional CAR-T cells. Mechanistically, C5/IL7-CAR-T cells displayed enhanced STAT5 signaling.
CONCLUSION
These findings highlight the potential of CXCR5 and IL-7 co-expression to improve CAR-T cell therapy efficacy against osteosarcoma.
论文信息
- 作者
- Hui X、Farooq MA、Chen Y、Ajmal I、Ren Y、Xue M、Ji Y、Du B
- 单位
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.China
- 期刊
- Frontiers in immunology2024
- 原文标识
- PubMed 39450160 · DOI 10.3389/fimmu.2024.1462076
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