2020 Fiscal Year Final Research Report

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

Research Project

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Project/Area Number	18K15319
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	Kobe University
Principal Investigator	Funakoshi Yohei 神戸大学, 医学部附属病院, 助教 (50566966)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	がん免疫 / PDXモデル / 免疫ヒト化 / 免疫チェックポイント阻害薬 / マイクロサテライト不安定性
Outline of Final Research Achievements	There has been an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies. Because conventional mouse models have limitations in cancer immunity research, we newly established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived PBMCs. PDX models were established from three patients with MSI-H CRC. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. PDX with the germline mutation (PDX1) was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H. When T cells from the same patient with MLH1 mutation were injected into the PDX1 through the tail vein, they were detected in the PDX tumor. Finally, we performed drug (anti PD-1 antibody) test by using humanized PDX1, and we found tendency for the increased number of infiltrating T cells.
Free Research Field	がん免疫
Academic Significance and Societal Importance of the Research Achievements	免疫チェックポイント阻害薬は、がん患者の生存期間の延長に寄与している。しかしながら、免疫チェックポイント阻害薬単剤の奏効割合は各がん種で概ね20%とその効果は限定的である。従って、更なるがん免疫および免疫療法の研究開発が必要であるが、現在の動物実験モデルではヒトがん免疫の再現が十分でないため、前臨床試験モデルを用いた免疫療法の薬効評価やバイオマーカーの探索を行うことが難しい。今回の研究は、ヒトのがん免疫をマウス内に再現することを目指したものである。これによりがん免疫療法の薬効評価が進めば、がん免疫療法の奏効率の上昇に寄与する研究が加速するものと考える。