The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei- MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei- MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, China; Department of Oral & Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Int Immunopharmacol. 2023 Jun;119:110243. doi: 10.1016/j.intimp.2023.110243. Epub 2023 May 1.
Enhancer of zeste homolog 2 (EZH2) is implicated in promoting HNSCC malignant progression. However, EZH2 inhibitors, when used alone, increase the number of myeloid-derived suppressor cells (MDSCs), which are responsible for enhancing tumor stemness and promoting tumor immune escape. We aimed to determine whether combining tazemetostat (an EZH2 inhibitor) and sunitinib (a MDSC inhibitor) can improve the response rate to an immune-checkpoint-blocking (ICB) therapy. We evaluated the efficacy of the above treatment strategies by bioinformatics analysis and animal experiments. EZH2 overexpression and abundant MDSCs in patients with HNSCC are associated with tumor progression. Tazemetostat treatment alone had limited inhibitory effect on HNSCC progression in the mouse models, accompanied by a surge in the number of MDSCs in the tumor microenvironment. Conversely, the combined use of tazemetostat and sunitinib reduced the number of MDSCs and regulatory T cell populations, promoting intratumoral infiltration of T cells and inhibiting of T cell exhausting, regulating of wnt/β-catenin signaling pathway and tumor stemness, promoting the intratumoral PD-L1 expression and improved the response rate to anti-PD-1 therapy. The combined use of EZH2 and MDSC inhibitors effectively reverses HNSCC-specific immunotherapeutic resistance and is a promising strategy for overcoming resistance to ICB therapy.
EZH2 是促进 HNSCC 恶性进展的重要因子。然而，EZH2 抑制剂单独使用时会增加髓系来源的抑制细胞（MDSC）的数量，而 MDSC 会增强肿瘤干性并促进肿瘤免疫逃逸。我们旨在确定联合使用 EZH2 抑制剂（tazemetostat）和 MDSC 抑制剂（sunitinib）是否可以提高免疫检查点阻断（ICB）治疗的反应率。我们通过生物信息学分析和动物实验评估了上述治疗策略的疗效。EZH2 过表达和 HNSCC 患者中丰富的 MDSC 与肿瘤进展相关。tazemetostat 单独治疗对小鼠模型中 HNSCC 的进展抑制作用有限，同时肿瘤微环境中 MDSC 的数量激增。相反，tazemetostat 和 sunitinib 的联合使用减少了 MDSC 和调节性 T 细胞的数量，促进了 T 细胞在肿瘤内的浸润，并抑制了 T 细胞衰竭、调节 wnt/β-catenin 信号通路和肿瘤干性，促进了肿瘤内 PD-L1 的表达，并提高了对抗 PD-1 治疗的反应率。EZH2 和 MDSC 抑制剂的联合使用有效地逆转了 HNSCC 特异性免疫治疗耐药性，是克服 ICB 治疗耐药性的一种有前途的策略。
