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Updated: Jun 9, 2025
Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
Characterizing dynamic tumor-immune interactions in lung adenocarcinoma through orthotopic allograft modeling
Mingjun Shi1, Tianqi Dong1, Jiaming Lin1
1Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
The major clinical challenge in lung cancer immunotherapy is drug resistance. Therefore, establishing efficient orthotopic lung cancer mouse models to explore the mechanisms of drug immunotherapy resistance is highly important. In this study, we generated multiple fluorescently labeled lung adenocarcinoma cell lines from a genetically engineered KPZ mice model. Orthotopic transplantation of the primary 1F3 cell line induced a strong immune response, causing many small tumors to disappear, but some tumors evaded the immune attack and eventually formed large tumors. Tumor microenvironment analysis demonstrated that M2 macrophages play key roles in the immune response. Further mechanistic studies revealed that the chemokine CCL7 promoted the infiltration of M2 macrophages to facilitate immune escape, thereby promoting tumor growth in the orthotopic mouse model. Moreover, CCL7 levels were elevated in human lung cancer biopsies and positively correlated with M2 macrophage infiltration, and high CCL7 levels predicted advanced pathological stage and poor survival in lung cancer patients. Overall, we established a visualized and orthotopic mouse model with fluorescently labeled cells to better dissect the tumor microenvironment of lung cancer and define the critical role of CCL7 in promoting M2 macrophage polarization and tumorigenesis, providing new preclinical tools and potential targets for lung cancer immunotherapy.
Insights
Drug resistance in lung cancer immunotherapy is a major hurdle. This study developed a novel mouse model revealing that chemokine CCL7 promotes M2 macrophage infiltration, aiding immune escape and tumor growth, offering new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Drug resistance significantly limits the efficacy of lung cancer immunotherapy.
- Developing effective orthotopic mouse models is crucial for studying immunotherapy resistance mechanisms.
Purpose of the Study:
- To establish a visualized orthotopic lung cancer mouse model to investigate tumor microenvironment and immunotherapy resistance.
- To identify key molecular mechanisms driving immune escape in lung cancer.
Main Methods:
- Generated fluorescently labeled lung adenocarcinoma cell lines from KPZ mice.
- Utilized orthotopic transplantation to create a lung cancer model.
- Analyzed tumor microenvironment, focusing on macrophage infiltration and chemokine signaling.
Main Results:
- The 1F3 cell line model demonstrated initial immune response followed by immune escape and tumor growth.
- M2 macrophages were identified as key players in the tumor immune response.
- Chemokine CCL7 was found to promote M2 macrophage infiltration, facilitating immune escape and tumor progression.
- Elevated CCL7 levels in human lung cancer biopsies correlated with M2 infiltration, advanced stage, and poor survival.
Conclusions:
- A novel, visualized orthotopic mouse model aids in dissecting lung cancer tumor microenvironments.
- CCL7 plays a critical role in promoting M2 macrophage polarization and tumorigenesis.
- CCL7 represents a potential therapeutic target for overcoming lung cancer immunotherapy resistance.
