An HNSCC syngeneic mouse model for tumor immunology research and preclinical evaluation
An HNSCC syngeneic mouse model for tumor immunology research and preclinical evaluation
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用于肿瘤免疫学研究和临床前评估的 HNSCC 同基因小鼠模型
DOI：
10.3892/ijmm.2020.4680
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发表时间：
2020-10-01
影响因子：
5.4
通讯作者：
Xu, Ke
中科院分区：
文献类型：
--
作者：
Fu, You;Tian, Guocai;Xu, Ke
缺乏可靠的动物模型来评估药物的安全性和有效性以及探索潜在的分子机制是头颈鳞状细胞癌（HNSCC）肿瘤免疫学研究中最严重的障碍之一。大多数使用免疫缺陷小鼠建立的异种移植肿瘤模型都忽略了 T 细胞的作用。迄今为止，据我们所知，还没有可以反映 HNSCC 肿瘤免疫微环境特征的同基因肿瘤模型。为了解决这个问题，本研究使用 4-硝基喹啉-1-氧化物 (4-NQO) 在 C57BL/6 小鼠中诱导鳞状细胞癌。随后建立了三种 HNSCC 细胞系，其中一种称为 JC1，因其在免疫缺陷裸鼠中增强的增殖能力和致瘤性而被选择用于进一步分析。然而，这 3 种细胞系均不能在免疫功能正常的小鼠中形成肿瘤。由于裸鼠和C57BL/6小鼠的致瘤性不同，免疫系统可能在接种的JC1肿瘤进展中发挥重要作用。采用化学诱导方法建立了致瘤性增强的细胞系JC1-2，该细胞系可以在免疫活性的C57BL/6小鼠中形成同系肿瘤。使用下一代测序 (NGS) 对 JC1-2 细胞进行免疫基因组和转录组表征。从 C57BL/6 小鼠中分离脾细胞并与 JC1-2 细胞共培养，以验证 JC1-2 细胞系中干扰素 (IFN)-γ 途径的反应性。与大多数同源小鼠肿瘤不同，JC1-2 形成的肿瘤类似于“炎症肿瘤”，因为肿瘤微环境中存在丰富的免疫细胞。此外，在原位小鼠模型中观察到比异位模型更强烈的免疫反应。因此，该模型可用于描述 HNSCC 和淋巴细胞之间的相互作用，并验证新的免疫治疗靶点。
y The lack of reliable animal models to assess the safety and efficacy of drugs and to explore the underlying molecular mechanisms is one of the most severe impediments in head and neck squamous cell carcinoma (HNSCC) tumor immunology research. The majority of xenograft tumor models established using immunodeficient mice neglect the effects of T cells. To date, to the best of our knowledge, there is no syngeneic tumor model available that reflects the immune microenvironmental features of HNSCC tumors. To solve this issue, the present study used 4-nitroquinoline-1-oxiyde (4-NQO) to induce squamous cell carcinoma in C57BL/6 mice. Three HNSCC cell lines were then established, and one of these, termed JC1, was selected for further analysis due to its enhanced proliferative ability and tumorigenicity in immunodeficient nude mice. However, none of the 3 cell lines could form tumors in immunocompetent mice. Due to the different tumorigenicities in nude and C57BL/6 mice, the immune system may play an important role in inoculated JC1 tumor progression. Chemical induction was used to establish the tumorigenicity-enhanced cell line, JC1-2, which can form syngeneic tumors in immunocompetent C57BL/6 mice. Next-generation sequencing (NGS) was used to perform the immunogenomic and transcriptomic characterization of the JC1-2 cells. Splenocytes were isolated from C57BL/6 mice and co-cultured with JC1-2 cells to verify the responsiveness of the interferon (IFN)-gamma pathway in the JC1-2 cell line. Unlike the majority of syngeneic mouse tumors, the JC1-2-formed tumors resembled 'inflamed tumors' due to the abundancy of immune cells in the tumor microenvironment. Moreover, more intense immune responses were observed in the orthotopic mouse model than in the heterotopic model. Thus, this model could be used to delineate the interactions between HNSCC and lymphocytes, and to validate novel immunotherapy targets.