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Updated: Jul 28, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
A T Cell-Engaging Tumor Organoid Platform for Pancreatic Cancer Immunotherapy
Zhuolong Zhou1, Kevin Van der Jeught1, Yujing Li1
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch DNA repair (dMMR), PDA is included in the most immune-resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, a high-throughput drug screen platform is established with the newly developed T cell-incorporated pancreatic tumor organoid model. Tumor-specific T cells are included in the pancreatic tumor organoids by two-step cell packaging, fully recapitulating immune infiltration in the immunosuppressive tumor microenvironment (TME). The organoids are generated with key components in the original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, and then packaged with T cells into their outside layer mimicking a physical barrier and enabling T cell infiltration and cytotoxicity studies. In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.
Insights
New pancreatic cancer organoid models enable drug discovery. Combining epigenetic inhibitors with immunotherapy significantly boosts anti-tumor effects by enhancing T cell activity in the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDA) is a difficult-to-treat cancer with poor response to current therapies, including immune checkpoint blockade (ICB).
- The immunosuppressive tumor microenvironment (TME) of PDA limits the efficacy of immunotherapies.
- Developing effective treatments for PDA requires innovative drug discovery platforms that model the complex TME.
Purpose of the Study:
- To establish a high-throughput drug screening platform for pancreatic ductal adenocarcinoma.
- To develop a novel T cell-incorporated pancreatic tumor organoid model that recapitulates the immunosuppressive TME.
- To identify novel therapeutic strategies for PDA by screening potential drug candidates.
Main Methods:
- Generation of pancreatic tumor organoids incorporating epithelial, vascular endothelial, fibroblast, and macrophage cells.
- Two-step cell packaging to include tumor-specific T cells, mimicking immune infiltration.
- Utilizing the organoid model for high-throughput drug screening and evaluating anti-tumor efficacy.
Main Results:
- Identification of epigenetic inhibitors ITF2357 and I-BET151 as promising agents.
- Combination therapy with epigenetic inhibitors and anti-PD-1 demonstrated significant anti-tumor effects.
- The combinatorial treatment modulated the TME from immunosuppressive to immunoactive, enhancing T cell function.
Conclusions:
- The T cell-incorporated pancreatic tumor organoid model is a valuable tool for accelerating drug discovery in PDA.
- Combination therapy targeting epigenetic pathways and immune checkpoints shows therapeutic potential for PDA.
- Modulating the TME to enhance T cell activity is a viable strategy for treating immune-resistant pancreatic cancer.
