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

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy
Title:
Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy
Other Titles:
Cancers
Publication Date:
22 April 2020
Citation:
Liu WN, Fong SY, Tan WWS, et al. Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy. Cancers (Basel). 2020;12(4):1025. Published 2020 Apr 22. doi:10.3390/cancers12041025
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-γ) 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-γ 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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This study was supported by the National Medical Research Council Singapore, CS-IRG (CIRG19may-0006) and NMRC/CSA-INV/0025/2017 to D.W.-T.L.; the VICTORY Programme (NMRC/OFLCG/003/2018), the Senior Clinician Scientist Award (CSA, NMRC/CSASI16nov006) and NMRC/TCR/015-NCC/2016, and by the National Research Foundation Singapore Fellowship (NRF-NRFF2017-03) and NRF-ISF joint grant (NRF2019-NRF-ISF003-3127) to Q.C., and also by A*STAR IAF-PP (H18/01/a0/022).
Description:
ISSN:
2072-6694
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