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<p>Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for hematological malignancies; however, its efficacy and safety remain challenging, particularly in the context of high tumor burden. High tumor load and substantial residual lesions significantly impair CAR T-cell function and exacerbate cytokine release syndrome (CRS). Here, we report the development of a novel dual cellular immunotherapy in which human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are co-administered with CD19 CAR T-cells. We demonstrated that this combination therapy enhances the anti-tumor efficacy of CD19 CAR T-cells under high tumor burden condition. In xenograft models of high tumor burden B-cell lymphoma, the dual cellular immunotherapy improved survival, mitigated myelosuppression, and preserved CAR T-cell expansion. Transcriptomic analysis of CAR T-cells revealed enrichment of the Th17 pathway in CAR T-cells, while single-cell RNA sequencing showed enhanced, particularly that of NK-like cytotoxic T lymphocytes characteristics which are associated with Th17 differentiation. Furthermore, in a CRS model, hUC-MSCs attenuate CRS severity by suppressing macrophage activity. Collectively, hUC-MSCs significantly enhance the anti-tumor capability of CD19 CAR T-cells under high tumor burden conditions by inducing CD8<sup>+</sup> NK-like cytotoxic T lymphocytes through Th17 differentiation, while concurrently mitigating treatment-related side effects. Our study provides a novel therapeutic strategy to improve clinical outcomes in hematological malignancies.</p>

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Th17-driven CD8+ T cells in hUC-MSC and CAR T-cell dual immunotherapy for superior anti-tumor efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Caidong Hu,
  • Haixiao Zhang,
  • Haojie Zhu,
  • Jixin Fan,
  • Dabing Chen,
  • Shuxian Zhu,
  • Chuo Li,
  • Jiaqi Sun,
  • Yifan Chen,
  • Jinhua Ren,
  • Xiaoming Feng,
  • Ying Chi,
  • Zhibo Han,
  • Zhongchao Han,
  • Erlie Jiang,
  • Guanbin Zhang,
  • Jianda Hu,
  • Ting Yang

摘要

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for hematological malignancies; however, its efficacy and safety remain challenging, particularly in the context of high tumor burden. High tumor load and substantial residual lesions significantly impair CAR T-cell function and exacerbate cytokine release syndrome (CRS). Here, we report the development of a novel dual cellular immunotherapy in which human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are co-administered with CD19 CAR T-cells. We demonstrated that this combination therapy enhances the anti-tumor efficacy of CD19 CAR T-cells under high tumor burden condition. In xenograft models of high tumor burden B-cell lymphoma, the dual cellular immunotherapy improved survival, mitigated myelosuppression, and preserved CAR T-cell expansion. Transcriptomic analysis of CAR T-cells revealed enrichment of the Th17 pathway in CAR T-cells, while single-cell RNA sequencing showed enhanced, particularly that of NK-like cytotoxic T lymphocytes characteristics which are associated with Th17 differentiation. Furthermore, in a CRS model, hUC-MSCs attenuate CRS severity by suppressing macrophage activity. Collectively, hUC-MSCs significantly enhance the anti-tumor capability of CD19 CAR T-cells under high tumor burden conditions by inducing CD8+ NK-like cytotoxic T lymphocytes through Th17 differentiation, while concurrently mitigating treatment-related side effects. Our study provides a novel therapeutic strategy to improve clinical outcomes in hematological malignancies.