Liu Wai Nam, Fong Shin Yie, Tan Wilson Wei Sheng, Tan Sue Yee, Liu Min, Cheng Jia Ying, Lim Sherlly, Suteja Lisda, Huang Edwin Kunxiang, Chan Jerry Kok Yen, Iyer Narayanan Gopalakrishna, Yeong Joe Poh Sheng, Lim Darren Wan-Teck, Chen Qingfeng
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore.
Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore.
Cancers (Basel). 2020 Apr 22;12(4):1025. doi: 10.3390/cancers12041025.
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.
免疫检查点阻断（ICB）单药治疗在鼻咽癌（NPC）患者的治疗中显示出早期前景。然而，有限的具有代表性的NPC模型阻碍了评估新型ICB及联合治疗方案疗效的临床前研究。在本研究中，我们将NPC活检组织移植到非肥胖糖尿病-严重联合免疫缺陷白细胞介素-2受体γ链基因敲除（NSG）小鼠体内，成功建立了人源化小鼠NPC患者来源异种移植（NPC-PDX）模型。通过爱泼斯坦-巴尔病毒编码的小RNA（EBER）原位杂交（ISH）和免疫组织化学（IHC）染色发现，NSG小鼠和人源化小鼠的NPC中均检测到爱泼斯坦-巴尔病毒。在携带NPC的人源化小鼠中，肿瘤浸润性CD8细胞毒性T细胞的百分比降低，且这些T细胞表达的各种抑制性受体水平高于血液中的T细胞，如程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）。然后用纳武单抗和伊匹单抗治疗这些小鼠，并检测联合免疫治疗的抗肿瘤疗效。与配对的临床数据一致，NPC-PDX在肿瘤负荷方面对治疗无反应，而在人源化小鼠中引发了免疫调节反应。根据我们的结果，人促炎细胞因子，如干扰素-γ（IFN-γ）和白细胞介素-6（IL-6）在血浆中显著上调。治疗后，NPC-PDX中的CD4/CD8比值降低，这也模拟了相应供体肿瘤内CD4/CD8谱的调节。此外，肿瘤浸润性T细胞被重新激活，并在体外刺激下分泌更多的IFN-γ，这表明包括可溶性介质和肿瘤微环境中的代谢环境在内的其他因素可能抵消ICB治疗的效果，并导致小鼠肿瘤进展。综上所述，我们建立并表征了一种新型的人源化小鼠NPC-PDX模型，该模型有望作为一个强大的平台来测试免疫治疗的疗效，并可能预测NPC患者的临床结果。
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