Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.

中文翻译：

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间充质干细胞通过 stanniocalcin-1 调节微环境来抑制 CAR-T 杀死淋巴瘤细胞的功效

干细胞在癌症的发展和治疗抵抗中都发挥着关键作用。尽管间充质干细胞 (MSCs) 可以主动迁移到肿瘤部位，但它们对 CAR-T 免疫疗法的影响却很少得到解决。使用包括淋巴瘤细胞和巨噬细胞在内的体外细胞共培养模型，我们报告在 MSCs 存在下，CAR-T 细胞介导的细胞毒性被显着抑制。MSC导致CD4+ T细胞和Treg细胞增加，但CD8+ T细胞减少。此外，间充质干细胞还刺激了吲哚胺 2,3-双加氧酶 (IDO) 和程序性细胞死亡配体 1 (PD-L1) 的表达，这有助于肿瘤的免疫抑制功能。此外，MSCs 通过调节线粒体 ROS 释放来抑制 NLRP3 炎性体的关键成分。有趣的是，如果编码糖蛋白激素 staniocalcin-1 的 STC1 基因在 MSC 中被敲低，那么所有这些阻碍 CAR-T 功效的抑制事件都可以被取消。使用异种移植小鼠，我们证实 CAR-T 功能也可以在体内被 MSC 抑制，而 STC1 发挥了关键作用。这些数据揭示了 MSC 和 staniocalcin-1 在抑制 CAR-T 疗效方面的新功能，应在癌症治疗中加以考虑，并可能在控制过度免疫反应引起的毒性方面具有潜在应用。