Neoadjuvant treatment strategy by anti-PD-1 immunotherapy combined with cisplatin inhibits recurrence and metastasis of NSCLC in a humanized mouse model
Received:March 23, 2022  
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DOI:10. 3969 / j.issn.1005-4847. 2022. 06. 003
KeyWord:humanized mouse model; non-small cell lung cancer; neoadjuvant therapy; pembrolizumab; cisplatin
李惠 1. 延安大学基础医学院,陕西 延安 ;2. 空军军医大学实验动物中心,西安
郭文文 空军军医大学实验动物中心,西安
王荟荟 2. 空军军医大学实验动物中心,西安 ;3. 甘肃中医药大学 基础医学院,兰州
秦靖 空军军医大学实验动物中心,西安
张彩勤 空军军医大学实验动物中心,西安
赵菊梅 延安大学基础医学院,陕西 延安
师长宏 空军军医大学实验动物中心,西安
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       Objective To investigate the effect of a neoadjuvant treatment strategy of an anti-PD-1 monoclonal antibody combined with cisplatin on postoperative recurrence and metastasis of non-small cell lung cancer (NSCLC) in a humanized mouse model. Methods Human peripheral blood mononuclear cells and human NSCLC cells were sequentially transplanted into the severe combined immunodeficiency mouse (NOD/ ShiLtJGpt-Prkdcem26Cd52 Il2rgem26Cd22 / Gpt, NCG) to establish an immune system-tumor double humanized NSCLC model. We elevated the treatment effect of various neoadjuvant strategies in the double humanized NSCLC model, including cisplatin, anti-PD-1 ( pembrolizumab), and combined treatments. Tumor recurrence and metastasis were observed by optical imaging. Ki67 expression in tumor tissue was analyzed by immunohistochemistry to assess tumor cell proliferation. Changes in the tumor immune microenvironment were detected by immunofluorescence. Results The double humanized NSCLC model was successfully established. Immune cells had infiltrated into peripheral blood, organs, and tumors. Optical imaging showed that neoadjuvant anti-PD-1 treatment inhibited tumor recurrence and metastasis, and the effect of combined treatment was more obvious. Moreover, combination treatment significantly decreased Ki67 expression in tumor tissues. Large numbers of CD8+ and CD45+ cells in tumors were observed after anti-PD-1 treatment, and many more CD8+ and CD45+ T cells were found in the combined therapy group. Granzyme B plays an important role in tumor killing by CD8+ T cells. Immunohistochemical staining showed that anti-PD-1 treatment increased granzyme B in tumor tissues, which was more obvious after combined treatment. Conclusions Neoadjuvant pembrolizumab combined with cisplatin effectively improves the anti-tumor effect in humanized mice and significantly inhibits tumor recurrence and metastasis.
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