肿瘤细胞治疗研究
英文原题：CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival.
嵌合抗原受体（CAR）T 细胞在血液系统恶性肿瘤中展现出卓越的治疗成功。
嵌合抗原受体（CAR）T 细胞在血液系统恶性肿瘤中已显示出卓越疗效，但由于细胞毒性 T 细胞和 CAR-T 细胞在肿瘤微环境（TME）中的浸润不足，其对实体瘤的疗效仍受限；这种浸润不足与实体瘤患者预后不佳相关。为克服这一局限，我们改造 CAR-T 细胞，使其分泌 CXCL10 和 IL-15（10 15 CAR-T），以维持 T 细胞活性并促进其募集，从而增强 CAR-T 细胞体外长期细胞毒能力。在采用 NUGC4-T21 细胞的异种移植模型中，与接受第二代 CAR-T 细胞的小鼠相比，接受 10 15 CAR-T 细胞的小鼠肿瘤缩小更多、生存率更高。组织病理学评估显示，10 15 CAR-T 细胞治疗后 TME 中细胞毒性 T 细胞积聚明显增加。因此，这些 CAR-T 细胞协同分泌 CXCL10 和 IL-15，可提高 T 细胞在肿瘤组织内的募集和适应能力，从而改善肿瘤控制。这一方法可能为推进 CAR-T 细胞疗法用于实体瘤治疗提供有前景的策略。
Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.
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