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Updated: Sep 17, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Suppression of multiple mouse models of refractory malignancies by reprogramming IL-18 ligand-receptor interaction
Zhen Fan1,2, Ying Liu3, Xueying Lin2
1Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Abstract:
Achieving a cure is an urgent need for patients with advanced solid tumors. Here, we discover that oncolytic virus (OV) infection enhances IL-18 receptor expression but fails to increase IL-18 ligand expression. Therefore, we engineer armed oncolytic alphavirus M1 expressing wild-type IL-18 (wtIL-18) or a mutant variant (mutIL-18) that evades IL-18 binding protein (IL-18BP) while maintaining IL-18 receptor (IL-18R) binding. Intravenous administration of M1-mutIL-18 suppresses the growth of multiple advanced solid tumors in C57BL/6 and BALB/c mouse models and promotes long-term systemic immune memory. Mechanistically, armed M1-mutIL-18 enhances directed clonal expansion and differentiation of CD8+ T cells and sustains IFN-γ production. Thus, armed M1-mutIL-18 promotes dendritic cell (DC) activation, priming and activation of CD8+ T cells in lymphatic organs, and infiltration of IL-18R+ CD8+ T cells in the tumor microenvironment, establishing a positive feedback loop. We further show that a PD-L1 inhibitor enhances the anti-tumor efficacy of mutIL-18 OVs. These results highlight the importance of the IL-18 pathway in oncolytic virus therapy and implicate reprogramming ligand-receptor interaction as an effective strategy for immunotherapy.
Insights
Engineered oncolytic viruses expressing a modified interleukin-18 (IL-18) ligand effectively treat advanced solid tumors by boosting CD8+ T cell responses and immune memory. This approach enhances immunotherapy for cancer treatment.
Area of Science:
- Immunotherapy
- Virology
- Oncology
Background:
- Advanced solid tumors lack effective cures, necessitating novel therapeutic strategies.
- Oncolytic viruses (OVs) can enhance anti-tumor immunity, but their efficacy is limited.
- Interleukin-18 (IL-18) signaling is crucial for T cell responses, but its therapeutic application is hindered by binding proteins.
Purpose of the Study:
- To engineer an oncolytic alphavirus (M1) to express a modified IL-18 variant (mutIL-18) that bypasses the IL-18 binding protein (IL-18BP).
- To evaluate the therapeutic efficacy of the engineered M1-mutIL-18 in preclinical models of advanced solid tumors.
- To elucidate the immunological mechanisms underlying the anti-tumor activity of M1-mutIL-18.
Main Methods:
- Engineering of oncolytic alphavirus M1 to express wild-type IL-18 (wtIL-18) or mutIL-18.
- Intravenous administration of engineered OVs in C57BL/6 and BALB/c mouse models with advanced solid tumors.
- Flow cytometry, immunohistochemistry, and cytokine analysis to assess immune cell populations, activation, and function.
- Combination therapy with a PD-L1 inhibitor.
Main Results:
- M1-mutIL-18 suppressed tumor growth and promoted long-term systemic immune memory in multiple solid tumor models.
- The therapy enhanced CD8+ T cell clonal expansion, differentiation, and sustained interferon-gamma (IFN-γ) production.
- M1-mutIL-18 promoted dendritic cell activation, T cell priming in lymphoid organs, and T cell infiltration into tumors, creating a positive feedback loop.
- Combination with a PD-L1 inhibitor further enhanced anti-tumor efficacy.
Conclusions:
- Engineered oncolytic viruses expressing IL-18 variants that evade IL-18BP represent a promising immunotherapy strategy.
- Reprogramming the IL-18 ligand-receptor interaction is a viable approach to enhance OV therapy.
- This strategy holds potential for treating advanced solid tumors by boosting T cell-mediated immunity.
