Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Advanced science, 2023-08, Vol.10 (23), p.e2300548-n/a

Ort / Verlag

Germany: John Wiley & Sons, Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.