Orthotopic model of pancreatic cancer using CD34+ humanized mice and generation of tumor organoids from humanized tumors

• Published in: International immunopharmacology 2023-08, Vol.121, p.110451-110451, Article 110451
• Main Authors: Hye Jeong, Ji, Park, Sujin, Lee, Sangyeon, Kim, Yeounhee, Kyong Shim, In, Jeong, Seong-Yun, Kyung Choi, Eun, Kim, Jinju, Jun, Eunsung
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD34; Disease Models, Animal; Humanized mice; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Organoids; Orthotopic model; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Tumor-derived organoids; Tumor-infiltrating immune cells; Xenograft Model Antitumor Assays
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.110451

•A humanized pancreas orthotopic model using CD34 + hHSC was successfully constructed.•The subtypes of human immune cells in blood and tumor were calculated and compared.•Immune cell numbers in tissue were correlated with the extracellular matrix density.•Primary cells and organoids were constructed from tissue were more immunogenic.•Useful for evaluating efficacy and high-throughput screening of oncology drugs. In pancreatic cancer (PC) as intractable solid cancer, current research is focused mainly on targeted immunotherapies such as antibodies and immune cell modulators. To identify promising immune-oncological agents, animal models that recapitulate the essential features of human immune status are essential. To this end, we constructed an orthotopic xenograft model using CD34+ human hematopoietic stem cell–based humanized NOD scid gamma mouse (NSG) mice injected with luciferase-expressing PC cell lines AsPC1 and BxPC3. The growth of orthotopic tumors was monitored using noninvasive multimodal imaging, while the subtype profiles of human immune cells in blood and tumor tissues were determined by flow cytometry and immunohistopathology. In addition, the correlations of blood and tumor-infiltrating immune cell count with tumor extracellular matrix density were calculated using Spearman’s test. Tumor-derived cell lines and tumor organoids with continuous passage capacity in vitro were isolated from orthotopic tumors. It was further confirmed that these tumor-derived cells and organoids have reduced PD-L1 expression and are suitable for testing the efficacy of specific targeted immunotherapeutic agents. These animal and culture models could facilitate the development and validation of immunotherapeutic agents for intractable solid cancers including PC.