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


1 Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, Kobe, Japan
2 Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine; Cancer Center, Kobe University Hospital, Kobe, Japan
3 Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan
4 Department of Medicine, Division of Gastroenterology, Kobe University Hospital and Graduate School of Medicine, Kobe, Japan
5 Department of Surgery, Division of Gastrointestinal Surgery, Kobe University Hospital and Graduate School of Medicine, Chuo-ku, Kobe, Japan

Correspondence Address:
Yohei Funakoshi,
Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017
Japan
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Source of Support: None, Conflict of Interest: None

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.


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