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NKG2D-CAR-targeted iPSC-derived MSCs efficiently target solid tumors expressing NKG2D ligand
Shuqing Tang1, Yusang Zhang1, Peiyun Wang1
1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
Abstract:
Mesenchymal stem cells (MSCs) hold potential in cancer therapy; however, insufficient tumor homing ability and heterogeneity limit their therapeutic benefits. Obviously, the homogeneous induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) with enhanced ability of tumor targeting could be the solution. In this study, a CAR containing the NKG2D extracellular domain was targeted at the B2M locus of iPSCs to generate NKG2D-CAR-iPSCs, which were subsequently differentiated into NKG2D-CAR-iMSCs. In vitro, NKG2D-CAR significantly enhanced migration and adhesion of iMSCs to a variety of solid tumor cells expressing NKG2D ligands. RNA sequencing (RNA-seq) revealed significant upregulation of genes related to cell adhesion, migration, and binding in NKG2D-CAR-iMSCs. In A549 xenograft model, NKG2D-CAR-iMSCs demonstrated a 57% improvement in tumor-homing ability compared with iMSCs. In conclusion, our findings demonstrate enhanced targeting specificity of NKG2D-CAR-iMSCs to tumor cells expressing NKG2D ligands in vitro and in vivo, facilitating future investigation of iMSCs as an off-the-shelf living carrier for targeted delivery of anti-tumor agents.
Insights
Engineered mesenchymal stem cells (iMSCs) show improved tumor targeting. These iMSCs, derived from induced pluripotent stem cells (iPSCs), enhance cancer therapy delivery by better homing to tumors.
Area of Science:
- Biotechnology
- Cancer Research
- Stem Cell Therapy
Background:
- Mesenchymal stem cells (MSCs) show promise in cancer therapy but suffer from poor tumor homing and heterogeneity.
- Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) offer a more homogeneous alternative.
- Enhancing iMSC tumor targeting is crucial for effective cancer treatment.
Purpose of the Study:
- To develop iMSCs with enhanced tumor targeting capabilities.
- To investigate the efficacy of NKG2D-chimeric antigen receptor (CAR) engineering in iMSCs.
- To evaluate the in vitro and in vivo homing and binding of engineered iMSCs to tumor cells.
Main Methods:
- Generated NKG2D-CAR-iPSCs by targeting the B2M locus in iPSCs.
- Differentiated NKG2D-CAR-iPSCs into NKG2D-CAR-iMSCs.
- Assessed in vitro migration and adhesion to tumor cells.
- Performed RNA sequencing to analyze gene expression changes.
- Evaluated tumor homing in an A549 xenograft mouse model.
Main Results:
- NKG2D-CAR engineering significantly enhanced iMSC migration and adhesion to tumor cells expressing NKG2D ligands.
- RNA-seq revealed upregulation of genes associated with cell adhesion and migration in NKG2D-CAR-iMSCs.
- NKG2D-CAR-iMSCs exhibited a 57% improvement in tumor homing compared to unmodified iMSCs in a xenograft model.
Conclusions:
- NKG2D-CAR-iMSCs demonstrate superior targeting specificity for tumor cells expressing NKG2D ligands.
- This engineered cell therapy shows potential as an off-the-shelf living carrier for targeted anti-cancer drug delivery.
- Further investigation into NKG2D-CAR-iMSCs is warranted for advancing cancer therapeutics.
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