Microsatellite instability-high colorectal cancer patient-derived xenograft models for cancer immunity research

• Published in: Journal of cancer research and therapeutics Vol. 17; no. 6; pp. 1358 - 1369
• Main Authors: Suto, Hirotaka, Funakoshi, Yohei, Nagatani, Yoshiaki, Imamura, Yoshinori, Toyoda, Masanori, Kiyota, Naomi, Matsumoto, Hisayuki, Tanaka, Shinwa, Takai, Ryo, Hasegawa, Hiroshi, Yamashita, Kimihiro, Matsuda, Takeru, Kakeji, Yoshihiro, Minami, Hironobu
• Format: Journal Article
• Language: English
• Published: India Wolters Kluwer India Pvt. Ltd 01.10.2021; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd
• Subjects: Aged; Aged, 80 and over; Animals; Apoptosis; Cancer; Care and treatment; Cell Proliferation; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; DNA Methylation; DNA Mismatch Repair; Female; Genetic aspects; Humans; Immunotherapy; Immunotherapy - methods; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Male; Mice; Mice, Inbred NOD; Mice, SCID; Microsatellite Instability; Middle Aged; Mutation; MutL Protein Homolog 1 - genetics; Oncology, Experimental; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenotransplantation; Japan; microsatellite instability; Cancer immunity research; sporadic methylation; germline mutation; patient-derived xenograft models
• ISSN: 0973-1482; 1998-4138; 1998-4138
• DOI: 10.4103/jcrt.JCRT_1092_20

Context: There is an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. Aims: Therefore, we established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived peripheral blood mononuclear cells (PBMCs). Subjects and Methods: The CRC tissues of patients scheduled for surgery were tested for MSI status, and CRC tumors were transplanted into NOD/LtSz-scid/IL-2Rg-/-(NSG) mice to establish MSI-H PDX models. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. To humanize the immune system of MSI-H PDX models, patient PBMCs were injected through the tail vein. Results: PDX models were established from two patients with MSI-H CRC; one patient had a germline mutation in MLH1 (c.1990-2A > G), and the other patient had MLH1 promoter hypermethylation. PDX with the germline mutation was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H, deficient mismatch repair (dMMR), and MLH1 mutation. In contrast, the histological features of the other PDX from a tumor with MLH1 promoter hypermethylation were clearly different from those of the original tumor, and MLH1 promoter hypermethylation and MSI-H/dMMR were lost in the PDX. When T cells from the same patient with MLH1 mutation were injected into the PDX through the tail vein, they were detected in the PDX tumor. Conclusions: The MSI-H tumor with an MMR mutation is suitable for MSI-H PDX model generation. The PBMC humanized MSI-H PDX has the potential to be used as an efficient model for cancer immunotherapy research.