Related Experiment Video
Updated: Apr 16, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Targeting the CCL2-CCR2 axis in cancer: insights into in vitro screening and humanized mice
1Department of Molecular Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan.
Abstract:
An immunosuppressive tumor microenvironment that facilitates cancer progression is an important challenge in combating the disease. The CCL2-CCR2 axis is a primary facilitator in this process, facilitating the recruitment of CCR2-positive myeloid cells, including M-MDSCs and TAMs, to tumor and metastatic locations. CCR2 is also expressed on tumor cells and regulatory T cells, further enhancing cancer cell motility and immune suppression. Inhibition of this system through genetic deletion or small-molecule inhibitors significantly reduces primary tumor and metastasis in preclinical models, highlighting CCR2 as a promising therapeutic target. Although several CCR2 inhibitors have entered clinical trials, differences in their potency and the limited predictability of murine models have hampered clinical translation. The current work by Sugiyama et al. carefully evaluated 10 human CCR2 antagonists, identifying MK0812 as the most effective inhibitor. Using human CCR2B knock-in mice, they established a practical platform for evaluating CCR2-targeted drugs with direct relevance to human cancer therapy, highlighting the importance of humanized models for translational immuno-oncology.
Insights
Researchers identified MK0812 as a potent CCR2 inhibitor, crucial for overcoming immunosuppressive tumor microenvironments. Humanized mouse models are vital for translating these immuno-oncology findings into effective cancer therapies.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The tumor microenvironment often suppresses anti-tumor immunity, promoting cancer progression.
- The CCL2-CCR2 pathway recruits immunosuppressive myeloid cells (M-MDSCs, TAMs) and impacts tumor cells and T regulatory cells.
- CCR2 is a validated therapeutic target, but clinical translation of inhibitors faces challenges due to model limitations.
Purpose of the Study:
- To evaluate human CCR2 antagonists for cancer therapy.
- To establish a predictive preclinical model for CCR2-targeted immuno-oncology drugs.
Main Methods:
- Screened 10 human CCR2 antagonists against the CCL2-CCR2 axis.
- Utilized human CCR2B knock-in mice to model humanized conditions.
- Assessed drug efficacy in reducing primary tumors and metastasis.
Main Results:
- Identified MK0812 as the most potent CCR2 inhibitor among those tested.
- Demonstrated the utility of humanized CCR2B knock-in mice for drug evaluation.
- Showcased the potential of CCR2 inhibition in preclinical cancer models.
Conclusions:
- MK0812 shows promise as a CCR2-targeted therapeutic agent.
- Humanized mouse models are essential for advancing translational immuno-oncology research.
- Targeting the CCL2-CCR2 axis offers a viable strategy against immunosuppressive tumors.
