共表达IL-7和CCL19的新抗原反应性T细胞在小鼠肺癌中的抗肿瘤研究
[Antitumor Study of Neoantigen-reactive T Cells Co-expressing IL-7 and CCL19 in Mouse Lung Cancer].
发表日期:2024 Jul 20
作者:
Di Wu, Chenhui Li, Yan Wang, Zhengqiang He, Chang'e Jin, Min Guo, Rongchang Chen, Chengzhi Zhou
来源:
CYTOKINE & GROWTH FACTOR REVIEWS
摘要:
新抗原反应性T细胞(NRT)具有抑制表达特定新抗原的肿瘤生长的能力。然而,由于免疫浸润困难以及肿瘤微环境的抑制,NRT对实体瘤的治疗效果有限。在本研究中,我们设计了能够在小鼠肺癌细胞中表达白细胞介素7(IL-7)和趋化因子C-C基序配体19(CCL19)的NRT细胞(7×19 NRT),并评估抗肿瘤效果的差异7×19 NRT细胞和常规NRT细胞之间的比较。我们对小鼠Lewis肺癌(LLC)进行了二代测序和新抗原预测,制备了RNA疫苗,培养了NRT细胞,构建了编码IL-7和CCL19的逆转录病毒载体,转导了NRT细胞成功表达IL-7和CCL19,成功获得7×19 NRT。在小鼠体内和体外评价抗肿瘤效果。7×19 NRT细胞通过分泌IL-7和CCL19显着增强T细胞的增殖和侵袭能力,对小鼠肺癌取得显着的抑瘤作用,并延长了T细胞的增殖和侵袭能力。小鼠的生存期。 7×19 NRT治疗后T细胞浸润肿瘤组织和肿瘤组织坏死明显增加。此外,7×19 NRT治疗和常规NRT治疗都是安全的。IL-7和CCL19的武装显着增强了NRT细胞的抗实体瘤能力,这是一种安全有效的NRT基因修饰。
Neoantigen reactive T cell (NRT) has the ability to inhibit the growth of tumors expressing specific neoantigens. However, due to the difficult immune infiltration and the inhibition of tumor microenvironment, the therapeutic effect of NRT in solid tumors is limited. In this study, we designed NRT cells (7×19 NRT) that can express both interleukin-7 (IL-7) and chemokine C-C motif ligand 19 (CCL19) in mouse lung cancer cells, and evaluated the difference in anti-tumor effect between 7×19 NRT cells and conventional NRT cells.We performed next-generation sequencing and neoantigen prediction for mouse Lewis lung carcinoma (LLC), prepared RNA vaccine, cultured NRT cells, constructed retroviral vectors encoding IL-7 and CCL19, transduced NRT cells and IL-7 and CCL19 were successfully expressed, and 7×19 NRT was successfully obtained. The anti-tumor effect was evaluated in vivo and in vitro in mice.The 7×19 NRT cells significantly enhanced the proliferation and invasion ability of T cells by secreting IL-7 and CCL19, achieved significant tumor inhibition in the mouse lung cancer and extended the survival period of mice. The T cell infiltration into tumor tissue and the necrosis of tumor tissue increased significantly after 7×19 NRT treatment. In addition, both 7×19 NRT treatment and conventional NRT treatment were safe.The anti-solid tumor ability of NRT cells is significantly enhanced by the arming of IL-7 and CCL19, which is a safe and effective genetic modification of NRT.