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Updated: Aug 24, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Mesothelin CAR-T cells secreting PD-L1 blocking scFv for pancreatic cancer treatment
Yeying Wang1, Xiaoyan Fang2, Minghao Li2
1Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P R China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P R China.
Abstract:
PD-1/PD-L1 pathway caused immunosuppression accounts, at least partly, for the poor therapeutic effect of Chimeric Antigen Receptor T (CAR-T) on solid tumors. In this study, we designed and prepared CAR-T cells that could secrete PD-L1 blocking antibody and target Mesothelin antigen (Sec-MesoCAR-T), to remove the immunosuppressive effect of tumor on CAR-T cells, thereby increasing the therapeutic effect of CAR-T cells on pancreatic cancer. The CAR-T cells that could not secret PD-L1 blocking antibodies (MesoCAR-T) were used as a control. Sec-MesoCAR-T cells showed an enhanced inhibitory effect on BxPC-3 tumor than MesoCAR-T cells in vitro and in vivo. Besides, Sec-MesoCAR-T cells secreted higher level of cytokines including IL-2, IL-6 and IFN-γ in vitro than MesoCAR-T cells. Following injection, there were significantly more CAR-T cells in the peripheral blood of Sec-MesoCAR-T group than that of MesoCAR-T group. This work demonstrated that the PD-L1 antibody secreted by Sec-MesoCAR-T cells relieved the immunosuppressive effect of pancreatic cancer on CAR-T cells and improved the anti-tumor activity of CAR-T cells, which has a good guiding significance for the clinical application of CAR-T cells in treating solid tumors.
Insights
Engineered CAR-T cells secreting PD-L1 antibodies enhance pancreatic cancer therapy by overcoming tumor-induced immunosuppression. This approach improves CAR-T cell persistence and anti-tumor activity in solid tumors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- The PD-1/PD-L1 pathway mediates immunosuppression, limiting the efficacy of Chimeric Antigen Receptor T (CAR-T) cell therapy in solid tumors.
- Pancreatic cancer exhibits a highly immunosuppressive tumor microenvironment, posing a significant challenge for CAR-T cell treatment.
Purpose of the Study:
- To develop novel CAR-T cells engineered to secrete a PD-L1 blocking antibody for targeting Mesothelin (Sec-MesoCAR-T).
- To evaluate the efficacy of Sec-MesoCAR-T cells in overcoming immunosuppression and enhancing anti-tumor activity against pancreatic cancer.
Main Methods:
- Designed and prepared Sec-MesoCAR-T cells capable of secreting PD-L1 blocking antibodies and targeting Mesothelin.
- Compared the in vitro and in vivo anti-tumor effects of Sec-MesoCAR-T cells against MesoCAR-T cells (control) in a pancreatic cancer model (BxPC-3).
- Assessed cytokine secretion (IL-2, IL-6, IFN-γ) and CAR-T cell persistence in peripheral blood.
Main Results:
- Sec-MesoCAR-T cells demonstrated superior tumor inhibition compared to MesoCAR-T cells in vitro and in vivo.
- Sec-MesoCAR-T cells secreted higher levels of key cytokines (IL-2, IL-6, IFN-γ).
- Significantly increased CAR-T cell numbers were observed in the peripheral blood of the Sec-MesoCAR-T group.
Conclusions:
- Engineered PD-L1 secretion by CAR-T cells effectively alleviates pancreatic cancer-induced immunosuppression.
- Sec-MesoCAR-T cells exhibit enhanced anti-tumor activity, offering a promising strategy for solid tumor treatment.
- This approach holds significant potential for advancing the clinical application of CAR-T cell therapy in solid malignancies.
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