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CSF1-CAR Specifically Targets CSF1R + Pancreatic Cancer Cells and Tumor-Associated Macrophages
Yongjie Zhu1, Ruipu Sun1, Jiawei Fan2
1Division of Abdominal Tumor Multimodality Treatment and Laboratory of Cell Engineering and Immunotherapy, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
A highly suppressive tumor immune microenvironment and nonspecific target endow malignant tumors with CAR-T cells. CSF1R is highly expressed on pancreatic cancer tissues compares with normal tissues in GEPIA database and M2 macrophages mainly contributing to the suppressive tumor microenvironment (TME), suggesting that CSF1R is a suitable antigen. CSF1 is the natural ligand of CSF1R, so we constructed a CSF1-CAR and tested its cytotoxic effect on tumor cells and macrophages in vitro. Our results demonstrated that CSF1-CAR-T cells can lyse tumor cells dependent on CSF1R expression. Meanwhile, CSF1-CAR-T also lyse CSF1R + M2 macrophages, suggesting that CSF1-CAR-T cells play a role in eliminating tumor cells and remodeling the TME.
Insights
Engineered CAR-T cells targeting CSF1R show promise for pancreatic cancer therapy. These cells effectively eliminate both tumor cells and suppressive M2 macrophages, remodeling the tumor microenvironment (TME).
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Malignant tumors often feature a suppressive tumor immune microenvironment (TME).
- Chimeric antigen receptor T-cell (CAR-T) therapy faces challenges with nonspecific targeting.
- CSF1R is highly expressed in pancreatic cancer and M2 macrophages, key components of a suppressive TME.
Purpose of the Study:
- To investigate CSF1R as a potential target for CAR-T cell therapy in pancreatic cancer.
- To evaluate the efficacy of a novel CSF1-CAR-T cell construct against tumor cells and M2 macrophages.
Main Methods:
- Constructed a Chimeric Receptor (CAR) targeting CSF1, the ligand for CSF1R.
- Tested the cytotoxic activity of CSF1-CAR-T cells against CSF1R-expressing tumor cells in vitro.
- Assessed the impact of CSF1-CAR-T cells on CSF1R-positive M2 macrophages.
Main Results:
- CSF1-CAR-T cells demonstrated specific lysis of tumor cells dependent on CSF1R expression.
- CSF1-CAR-T cells effectively lysed CSF1R-positive M2 macrophages.
- These findings suggest a dual role for CSF1-CAR-T cells in tumor elimination and TME modulation.
Conclusions:
- CSF1R is a viable target for CAR-T cell therapy in pancreatic cancer.
- CSF1-CAR-T cells can eliminate both pancreatic cancer cells and immunosuppressive M2 macrophages.
- This approach holds potential for remodeling the tumor microenvironment and enhancing therapeutic outcomes.
