Journal Article

A T Cell‐Engaging Tumor Organoid Platform for Pancreatic Cancer Immunotherapy

Lu, Xiongbin, Liu, Sheng, Opyrchal, Mateusz, Territo, Paul R., Wan, Guohui, Van der Jeught, Kevin, Moulana, Ishara, Wan, Jun, Zhang, Xinna, Zhou, Zhuolong, Li, Yujing, Sharma, Samantha, Yu, Tao

2023

Overview

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. Pancreatic ductal adenocarcinoma is one of the most immune‐resistant cancer types. To combat this immunosuppressive tumor type, a new T cell‐incorporated pancreatic tumor organoid model is established, fully recapitulating immune infiltration in the tumor microenvironment. In a drug screen, epigenetic inhibitors, ITF2357, and I‐BET151 are identified, which significantly promote the efficacy of anti‐PD‐1 based immune checkpoint blockade therapy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Antigens / Cancer therapies / Carcinoma, Pancreatic Ductal - drug therapy / Chemotherapy / Cytotoxicity / epigenetic inhibitors / Epigenetics / Fibroblasts / Genes / high‐throughput drug screen / Humans / Immunotherapy / Lymphocytes / Organoids - pathology / Pancreatic cancer / pancreatic ductal adenocarcinoma / Pancreatic Neoplasms - drug therapy / patient‐derived organoid / T-Lymphocytes / tumor antigen presentation / Tumor Microenvironment / tumor organoid / Tumors