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An improved cell line-derived xenograft humanized mouse model for evaluation of PD-1/PD-L1 blocker BMS202-induced immune responses in colorectal cancer.

ABSTRACT: The establishment of an in vivo mouse model mimicking human tumor-immune environments provides a promising platform for immunotherapy assessment, drug discovery and clinical decision guidance. To this end, we construct humanized NCG mice by transplanting human hCD34 ⁺ hematopoietic progenitors into non-obese diabetic (NOD) Cg- Prkdc ^scidIL2rg ^tm1Wjl /Sz (null; NCG) mice and monitoring the development of human hematopoietic and immune systems (Hu-NCG). The cell line-derived xenograft (CDX) Hu-NCG mouse models are set up to assess the outcome of immunotherapy mediated by the small molecule BMS202. As a PD-1/PD-L1 blocker, BMS202 shows satisfactory antitumour efficacy in the HCT116 and SW480 xenograft Hu-NCG mouse models. Mechanistically, BMS202 exerts antitumour efficacy by improving the tumor microenvironment and enhancing the infiltration of hCD8 ⁺ T cells and the release of hIFNγ in tumor tissue. Thus, tumor-bearing Hu-NCG mice are a suitable and important in vivo model for preclinical study, particularly in cancer immunotherapy.

SUBMITTER: Shang P

PROVIDER: S-EPMC9827804 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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An improved cell line-derived xenograft humanized mouse model for evaluation of PD-1/PD-L1 blocker BMS202-induced immune responses in colorectal cancer.

Shang Pengzhao P Yu Liting L Cao Shucheng S Guo Changying C Zhang Wanheng W

Acta biochimica et biophysica Sinica 20221001 10

The establishment of an in vivo mouse model mimicking human tumor-immune environments provides a promising platform for immunotherapy assessment, drug discovery and clinical decision guidance. To this end, we construct humanized NCG mice by transplanting human hCD34 + hematopoietic progenitors into non-obese diabetic (NOD) Cg- Prkdc scidIL2rg tm1Wjl /Sz (null; NCG) mice and monitoring the development of human hematopoietic and immune systems (Hu-NCG ...[more]

PMID: 36269133

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Project description:BackgroundBreast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models.MethodsTo circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3-4-week-old mice. After both PDXs and melanoma cell xenografts reached ~ 150-200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action.ResultsHuman CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~ 85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models.ConclusionsThis study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.

Dataset Information

An improved cell line-derived xenograft humanized mouse model for evaluation of PD-1/PD-L1 blocker BMS202-induced immune responses in colorectal cancer.

Publications

An improved cell line-derived xenograft humanized mouse model for evaluation of PD-1/PD-L1 blocker BMS202-induced immune responses in colorectal cancer.

Similar Datasets

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