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Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy.

ABSTRACT: Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein-Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein-Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-?) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-? towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients.

SUBMITTER: Liu WN

PROVIDER: S-EPMC7225949 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy.

Liu Wai Nam WN Fong Shin Yie SY Tan Wilson Wei Sheng WWS Tan Sue Yee SY Liu Min M Cheng Jia Ying JY Lim Sherlly S Suteja Lisda L Huang Edwin Kunxiang EK Chan Jerry Kok Yen JKY Iyer Narayanan Gopalakrishna NG Yeong Joe Poh Sheng JPS Lim Darren Wan-Teck DW Chen Qingfeng Q

Cancers 20200422 4

Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model ...[more]

PMID: 32331230

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Project description:The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients.

Dataset Information

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy.

Publications

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy.

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