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Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Engineered iMSCs delivering wild-type IL-2 achieve dose-sparing tumor control via CD25-dependent CD8+ T-cell
Shuqing Tang1,2, Mengting Han1, Peiyun Wang1
1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China.
BMC Medicine
|June 29, 2026
Summary
Genetically engineered mesenchymal stromal cells (iMSCs) deliver Interleukin-2 (IL-2) to enhance T-cell activation and tumor control while reducing toxicity. This novel gene therapy platform improves safety and efficacy for cancer treatment.
Area of Science:
- Immunotherapy
- Gene Therapy
- Cancer Research
Background:
- Interleukin-2 (IL-2) is a cytokine immunotherapy with antitumor potential but limited by severe toxicities.
- Mesenchymal stromal cells (MSCs) are being explored as delivery vehicles for IL-2 due to their tumor-homing and low immunogenicity.
- Developing safer and more effective IL-2 delivery methods is crucial for clinical translation.
Purpose of the Study:
- To engineer mesenchymal stromal cells (MSCs) to secrete Interleukin-2 (IL-2) for enhanced cancer immunotherapy.
- To evaluate the antitumor efficacy and safety profile of IL-2 secreting iMSCs in preclinical models.
- To investigate the mechanism of action of iMSC-delivered IL-2 on the tumor microenvironment.
Main Methods:
- Human induced pluripotent stem cells (iPSCs) were genetically modified using CRISPR/Cas9 to express wild-type IL-2 (wtIL-2) or a variant, creating iPSC-derived MSCs (iMSCs).
- Antitumor activity was assessed in vitro via co-cultures and in vivo using mouse models with subcutaneous tumors.
- Biodistribution, tumor targeting, tumor control, and systemic toxicity were evaluated, alongside immune cell profiling within the tumor microenvironment.
Main Results:
- iMSCs engineered for IL-2 overexpression induced CD25 upregulation on CD8+ T cells, enhancing sensitivity to IL-2 and improving tumor control at lower doses.
- Systemic administration of wtIL-2-iMSCs activated intratumoral T cells, inhibited tumor growth comparably to high-dose IL-2, and reduced systemic toxicity.
- Targeted IL-2 integration at the B3 locus (B3-wtIL-2-iMSCs) enhanced antitumor activity and showed synergistic effects with anti-PD-1 blockade.
Conclusions:
- iMSC-delivered IL-2 reshapes the tumor microenvironment by activating CD8+ T cells in a CD25-dependent manner.
- This platform offers a dose-efficient cytokine delivery strategy with an improved safety profile for cancer immunotherapy.
- The findings support the clinical translation of off-the-shelf allogeneic iMSC-based gene therapies.
