{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:39:44Z","timestamp":1790739584424,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,22]],"date-time":"2020-04-22T00:00:00Z","timestamp":1587513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Medical Research Council Singapore, CS-IRG","award":["CIRG19may-0051"],"award-info":[{"award-number":["CIRG19may-0051"]}]},{"name":"VICTORY Programme","award":["NMRC\/OFLCG\/003\/2018"],"award-info":[{"award-number":["NMRC\/OFLCG\/003\/2018"]}]},{"name":"Senior Clinician Scientist Award, CSA","award":["NMRC\/CSASI16nov006"],"award-info":[{"award-number":["NMRC\/CSASI16nov006"]}]},{"name":"National Medical Research Council Singapore","award":["NMRC\/TCR\/015-NCC\/2016"],"award-info":[{"award-number":["NMRC\/TCR\/015-NCC\/2016"]}]},{"name":"National Research Foundation Singapore Fellowship","award":["NRF-NRFF2017-03"],"award-info":[{"award-number":["NRF-NRFF2017-03"]}]},{"name":"NRF-ISF joint grant","award":["NRF2019-NRF-ISF003-3127"],"award-info":[{"award-number":["NRF2019-NRF-ISF003-3127"]}]},{"name":"A*STAR IAF-PP","award":["H18\/01\/a0\/022"],"award-info":[{"award-number":["H18\/01\/a0\/022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\u2013Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein\u2013Barr 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-\u03b3) 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-\u03b3 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.<\/jats:p>","DOI":"10.3390\/cancers12041025","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T02:10:52Z","timestamp":1587607852000},"page":"1025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4323-4566","authenticated-orcid":false,"given":"Wai Nam","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin Yie","family":"Fong","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3027-1162","authenticated-orcid":false,"given":"Wilson Wei Sheng","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue Yee","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Ying","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherlly","family":"Lim","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisda","family":"Suteja","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin Kunxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, KK Women\u2019s and Children\u2019s Hospital, Singapore 229899, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry Kok Yen","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, KK Women\u2019s and Children\u2019s Hospital, Singapore 229899, Singapore"},{"name":"Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8812-6219","authenticated-orcid":false,"given":"Narayanan Gopalakrishna","family":"Iyer","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe Poh Sheng","family":"Yeong","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Agency for Science, 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Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nrc.2016.92","article-title":"Epstein\u2013Barr virus: More than 50 years old and still providing surprises","volume":"16","author":"Young","year":"2016","journal-title":"Nat. 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