CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
分泌 Relaxin-2 的 CAR-T 细胞在富含基质异种移植瘤中显示增强疗效
英文原题：Relaxin-2-secreting CAR-T cells exhibit enhanced efficacy in stromal-rich xenograft tumors.
查看英文原题
Relaxin-2-secreting CAR-T cells exhibit enhanced efficacy in stromal-rich xenograft tumors.
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研究概要
RLN2 可能通过促进 CAR-T 细胞浸润到肿瘤微环境，增强其对抗实体瘤的抗肿瘤活性。
研究思路结论见上方概要
嵌合抗原受体（CAR）-T细胞疗法在治疗血液系统恶性肿瘤方面已显示出显著疗效。尽管其在实体瘤的临床管理中展现出前景，但临床试验中的不佳结果凸显了开发适用于独特肿瘤微环境的疗法所面临的挑战，该微环境以由成纤维细胞和细胞外基质蛋白（如胶原蛋白、透明质酸、蛋白聚糖、层粘连蛋白和弹性蛋白）构成的致密基质为特征。这些主要由成纤维细胞产生的成分形成了一道屏障，可阻碍CAR-T 细胞向肿瘤内浸润，从而限制其疗效。从肿瘤血管迁移至基质中的CAR-T 细胞可能在到达肿瘤细胞之前即被困住。
我们将CAR-T 细胞工程化改造为分泌松弛素-2（RLN2），一种抗纤维化肽类激素。RLN2以其在妊娠中的作用而闻名，可促进宫颈和骨盆韧带中胶原的软化和重塑，并通过与受体LGR7/RXFP1结合上调基质金属蛋白酶水平，从而促进肿瘤微环境中的胶原降解。
体外研究显示，暴露于CAR-T 细胞分泌的RLN2的癌细胞表现出特定基质金属蛋白酶表达和分泌增加。在基质含量丰富的小鼠异种移植模型中，与常规CAR-T 细胞相比，分泌RLN2的CAR-T 细胞表现出显著改善的抗肿瘤疗效和对肿瘤微环境的浸润。
展开英文摘要原文
We engineered CAR-T cells to secrete relaxin-2 (RLN2), an antifibrotic peptide hormone. Known for its role in pregnancy, RLN2 facilitates the softening and remodeling of collagen in the cervix and pelvic ligaments, and also promotes collagen degradation in the tumor microenvironment by upregulating matrix metalloproteinase levels by binding to the receptor LGR7/RXFP1.
In vitro studies revealed that cancer cells exposed to CAR-T cell-secreted RLN2 exhibited an increased expression and secretion of specific matrix metalloproteinases. In mouse xenograft models with abundant stromal content, RLN2-secreting CAR-T cells demonstrated significantly improved antitumor efficacy and infiltration into the tumor microenvironment compared to conventional CAR-T cells. DISCUSSION: RLN2 may enhance the antitumor activity of CAR-T cells against solid tumors by promoting their infiltration into the tumor microenvironment.
论文信息
- 作者
- Ogawa H、Ekawa T、Mizote Y、Akazawa T、Tahara H
- 第一作者单位
- Nitto Joint Research Department for Nucleic Acid Medicine, Research Center, Osaka International Cancer Institute, Osaka, Japan.Japan
- 通讯作者单位
- Department of Cancer Drug Discovery and Development, Research Center, Osaka International Cancer Institute, Osaka, Japan.Japan
- 期刊
- Frontiers in immunology2025
- 原文标识
- PubMed 40666525 · DOI 10.3389/fimmu.2025.1506204