PO.CL05.10 · 临床研究
IL-24工程化间充质干细胞作为重塑非小细胞肺癌肿瘤微环境的新型治疗策略
IL-24 engineered mesenchymal stem cells as a novel therapeutic strategy to remodel the tumor microenvironment in non-small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
非小细胞肺癌（NSCLC）中免疫检查点抑制剂（ICI）耐药常由免疫抑制性肿瘤微环境（TME）驱动。为解决这一问题，我们开发了IL-24-iMSC，一种基于间充质干细胞的新型疗法，旨在通过持续分泌白细胞介素24（IL-24，一种具有抗癌特性的免疫调节细胞因子）来重塑免疫抑制性肿瘤微环境。诱导性间充质干细胞（iMSC）来源于诱导多能干细胞（iPSC），并使用CRISPR/Cas技术将IL-24基因整合到iMSC的B2M位点，置于EF1alpha启动子的控制之下。IL-24-iMSC被证实可组成性分泌IL-24。通过将表达荧光素酶的Lewis肺癌细胞（LLC-luc）尾静脉注射到免疫功能正常的C57BL/6小鼠中，建立了转移性肺癌模型。使用活体成像系统（IVIS）监测肿瘤进展。治疗于肿瘤接种20天后给予，小鼠被随机分为三组：iMSC、IL-24-iMSC或载体对照。所有小鼠在治疗3天后处死。通过IVIS生物发光成像确认肿瘤生长，并采集肿瘤样本进行免疫分析。虽然三组之间肿瘤生长无显著差异，但暴露于IL-24-iMSC的肿瘤表现出促炎表型。多重免疫组织化学证实MSC浸润到TME中，IL-24-iMSC组IL-24表达显著增加。与对照组（未治疗）相比，接受IL-24-iMSC治疗的肿瘤显示CD8+ T细胞、树突状细胞和记忆性CD4+ T细胞增加。IL-24-iMSC治疗组的IFN-gamma和TNF-alpha表达也升高。相反，IL-24-iMSC组的调节性T细胞和耗竭性T细胞（PD1+ TIM3+）显著减少。总之，IL-24-iMSC展示了调节肿瘤微环境内免疫细胞组成的能力，提示其在NSCLC中与ICI协同的潜力。
查看英文原文 English abstract
Immune checkpoint inhibitor (ICI) resistance in non-small cell lung cancer (NSCLC) is frequently driven by an immunosuppressive tumor microenvironment (TME). To address this issue, we developed IL-24-iMSC, a novel mesenchymal stem cell-based therapy designed to remodel the immunosuppressive tumor microenvironment through sustained secretion of interleukin 24 (IL-24), an immunomodulatory cytokine with anti-cancer properties. Induced mesenchymal stem cells (iMSCs) were derived from induced pluripotent stem cells (iPSCs) and the IL-24 gene was integrated into iMSC at the B2M locus under the control of the EF1alpha promoter using CRISPR/Cas. IL-24-iMSCs were confirmed to constitutively secrete IL-24. Metastatic lung cancer models were established by tail vein injection of Lewis Lung Carcinoma cells expressing luciferase (LLC-luc) into immunocompetent C57BL/6 mice. Tumor progression was monitored using an In Vivo Imaging System (IVIS). Treatment was administered 20 days after tumor inoculation, and mice were randomized into three groups: iMSC, IL-24-iMSC, or vehicle control. All mice were sacrificed three days after treatment. Tumor growth was confirmed by bioluminescence imaging using IVIS, and tumor samples were collected for immune profiling. While there was no significant difference in tumor growth among the three groups, tumors exposed to IL-24-iMSC demonstrated a pro-inflammatory phenotype. Multiplex immunohistochemistry confirmed infiltration of MSCs into the TME, with significantly increased IL-24 expression in the IL-24-iMSC arm. Compared with the control group (untreated), tumors treated with IL-24-iMSC showed increased CD8+ T cells, dendritic cells, and memory CD4+ T cells. IFN-gamma and TNF-alpha expressions were also elevated in the IL-24-iMSC treatment arm. On the contrary, regulatory T cells and exhausted T cells (PD1+ TIM3+) were significantly reduced in the IL-24-iMSC group. In conclusion, IL-24-iMSCs demonstrated the ability to modulate immune cell composition within the tumor microenvironment, suggesting their potential to synergize with ICI in NSCLC.
利益披露 Disclosure
Y. Zhang, None..
Y. Zhang, None..
T. Kwong, None..
D. Liang, None.