Effect of regorafenib, anti-PD1, and anti-CD40 agonist in Head and Neck Squamous Cell Carcinoma [4NQO_model]

Regorafenib presented an antitumor activity in HNSCC mouse model and delayed the tumorigenesis of the 4NQO-indued oral mouse model. By tumor-infiltration lymphocytes isolation and RNA-seq analysis, the immunity-related function was activated by regorafenib. We approved that regorafenib can determine the macrophage polarization toward M1 inflammatory macrophages by suppressing the production of certain cytokines such as plasminogen activator inhibitor-1 (PAI-I) from tumor cells. Also, Regorafenib suppresses secretion of PAI-1 from ex vivo cultures of human HNSCC organoids. Overall design: We performed RNA-seq on tumors from HNSCC mouse model and 4NQO-indued oral mouse model with the treatment of vehicle control, regorafenib, anti-PD1, and regorafenib + anti-PD1

瑞戈非尼（Regorafenib）在头颈部鳞状细胞癌（Head and Neck Squamous Cell Carcinoma, HNSCC）小鼠模型中展现出显著的抗肿瘤活性，同时可延缓4NQO诱导的口腔小鼠模型的肿瘤发生进程。通过肿瘤浸润淋巴细胞分离与RNA测序（RNA-seq）分析，我们证实瑞戈非尼可激活免疫相关功能通路。本研究明确，瑞戈非尼可通过抑制肿瘤细胞分泌纤溶酶原激活物抑制剂-1（PAI-1）等细胞因子，诱导巨噬细胞极化为M1型炎性巨噬细胞。此外，瑞戈非尼可抑制人HNSCC类器官离体培养体系中PAI-1的分泌。整体实验设计：我们对经赋形剂对照、瑞戈非尼、抗PD-1以及瑞戈非尼联合抗PD-1处理的HNSCC小鼠模型与4NQO诱导的口腔小鼠模型的肿瘤组织，开展了RNA测序分析。