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Updated: Aug 29, 2026
Natural Killer (NK) and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
Published on: February 8, 2022
In vivo antitumor activity of interleukin 21 mediated by natural killer cells
Gang Wang1, Mary Tschoi, Rosanne Spolski
1Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. gangwang@mdanderson.org
Abstract:
Immunotherapy with high-dose interleukin (IL) 2 has been shown to successfully treat tumors in animal models and cause dramatic tumor regressions in some patients with metastatic melanoma, renal cell carcinoma, and non-Hodgkin's lymphoma. However, toxicity associated with IL-2 administration has compromised its widespread use in the clinic. IL-21 is a more recently discovered cytokine produced by activated CD4(+) T cells that shares significant sequence homology to IL-2, IL-4, and IL-15. Because IL-21 and IL-2 and their receptors share significant sequence similarities and both cytokines can stimulate T and natural killer (NK) cells, we sought to study whether IL-21, like IL-2, exhibits antitumor effects in vivo. In this study, we treated established s.c. tumor in mice by systemically administering plasmid DNA encoding murine IL-21 using a hydrodynamics-based gene delivery technique. Administration of IL-21 plasmid DNA resulted in high levels of circulating IL-21 in vivo. Treatment of tumor-bearing mice with IL-21 plasmid DNA significantly inhibited the growth of B16 melanoma and MCA205 fibrosarcoma in a dose-dependent manner without significant toxicity and increased the survival rate, compared with mice treated with control plasmid DNA. In vivo depletion of either CD4(+) or CD8(+) T cells did not affect IL-21-mediated antitumor activity. However, depletion of NK cells completely abolished IL-21-induced tumor inhibition. Consistent with this, the antitumor activity of IL-21 seemed to be mediated through enhanced cytolytic activity of NK cells. Our study suggests that IL-21 has significant antitumor activity and may have therapeutic potentials as an antitumor agent in the clinic.
Insights
Interleukin-21 (IL-21) demonstrates significant antitumor effects in mice by enhancing natural killer cell activity. This cytokine shows therapeutic potential for cancer treatment with reduced toxicity compared to Interleukin-2 (IL-2).
Area of Science:
- Immunology
- Cancer Biology
- Gene Therapy
Background:
- High-dose Interleukin-2 (IL-2) immunotherapy shows efficacy against certain cancers but causes significant toxicity.
- Interleukin-21 (IL-21) is a cytokine sharing similarities with IL-2, potentially offering similar antitumor benefits with improved safety.
- The antitumor mechanisms of IL-21, particularly its role in innate and adaptive immunity, require further investigation.
Purpose of the Study:
- To investigate the in vivo antitumor efficacy of Interleukin-21 (IL-21).
- To determine the cellular mechanisms underlying IL-21's potential antitumor activity.
- To assess the safety and therapeutic potential of IL-21 gene therapy.
Main Methods:
- Systemic administration of plasmid DNA encoding murine IL-21 via hydrodynamic gene delivery in tumor-bearing mice.
- Dose-dependent evaluation of IL-21 plasmid DNA treatment on tumor growth (B16 melanoma, MCA205 fibrosarcoma).
- In vivo cell depletion studies targeting CD4+ T cells, CD8+ T cells, and NK cells to elucidate IL-21's mechanism of action.
Main Results:
- IL-21 plasmid DNA administration led to elevated circulating IL-21 levels and significantly inhibited tumor growth in a dose-dependent manner.
- IL-21 treatment increased survival rates without significant observable toxicity.
- Antitumor activity was independent of CD4+ and CD8+ T cells but was completely abolished by NK cell depletion, indicating NK cell-mediated effects.
Conclusions:
- Interleukin-21 (IL-21) exhibits potent in vivo antitumor activity against established tumors.
- The antitumor effects of IL-21 are primarily mediated through the enhanced cytolytic activity of natural killer (NK) cells.
- IL-21 represents a promising candidate for novel cancer immunotherapy with potential clinical applications.
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