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Updated: Jun 28, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular
Wei Zhu1, Zhiming Zhang1, Jinzhang Chen1
1State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.
Insights
Interleukin-21 (IL-21) enhances T cell receptor-engineered T cell (TCR-T) therapy against liver cancer. A novel engineered IL-21 receptor improves TCR-T function and reduces exhaustion for better solid tumor treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T cell therapy efficacy in solid tumors like hepatocellular carcinoma (HCC) needs improvement.
- Cytokines like IL-21 are crucial for T cell development and function.
- Optimizing IL-21 signaling is key for enhancing T cell therapies.
Purpose of the Study:
- To evaluate the combined effects of IL-21 on T cell therapy for HCC.
- To investigate strategies for optimizing IL-21 signal utilization in T cell therapy.
- To develop a novel engineered IL-21 receptor for enhanced T cell function.
Main Methods:
- Exogenous IL-21 was used to augment AFP-specific T cell receptor-engineered T cells (TCR-T) in vitro and in vivo.
- A novel engineered IL-21 receptor was created and incorporated into TCR-T (IL-21R-TCR-T).
- Phenotypic and functional analyses of IL-21R-TCR-T were performed, including proliferation, differentiation, exhaustion markers, and antitumor activity.
Main Results:
- Exogenous IL-21 enhanced TCR-T proliferation, memory differentiation, and antitumor activity, while reducing PD-1 expression and apoptosis.
- IL-21R-TCR-T exhibited constitutive STAT3 phosphorylation without exogenous IL-21.
- IL-21R-TCR-T demonstrated superior proliferation, enhanced antitumor function, and a less exhausted phenotype compared to conventional TCR-T upon repeated antigen stimulation.
Conclusions:
- A novel engineered IL-21 receptor can program potent TCR-T cells for HCC treatment.
- This approach enhances T cell function and avoids systemic IL-21 side effects.
- The engineered IL-21 receptor offers a promising strategy for next-generation T cell therapies against solid tumors.
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