Sunitinib attenuates reactive MDSCs enhancing anti-tumor immunity in HNSCC
Sunitinib attenuates reactive MDSCs enhancing anti-tumor immunity in HNSCC
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DOI：
10.1016/j.intimp.2023.110243
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发表时间：
2023-05-01
影响因子：
5.6
通讯作者：
Sun，Zhi-Jun
中科院分区：
文献类型：
--
作者：
Liu，Jie;Lin，Wen -Ping;Sun，Zhi-Jun
zeste增强子同源物2（EZH 2）参与促进HNSCC恶性进展。然而，EZH 2抑制剂单独使用时，会增加髓源性抑制细胞（MDSC）的数量，这些细胞负责增强肿瘤干细胞和促进肿瘤免疫逃逸。我们的目的是确定联合tazemetostat（EZH 2抑制剂）和舒尼替尼（MDSC抑制剂）是否可以提高对免疫检查点阻断（ICB）治疗的应答率。我们通过生物信息学分析和动物实验来评估上述治疗策略的疗效。HNSCC患者中EZH 2过表达和丰富的MDSC与肿瘤进展相关。单独的Tazemetostat治疗对小鼠模型中的HNSCC进展具有有限的抑制作用，伴随着肿瘤微环境中MDSC数量的激增。相反，联合使用tazemetostat和舒尼替尼可减少MDSC和调节性T细胞群的数量，促进肿瘤内T细胞浸润并抑制T细胞耗竭，调节wnt/β-catenin信号通路和肿瘤干细胞，促进肿瘤内PD-L1表达，提高抗PD-1治疗的应答率。EZH 2和MDSC抑制剂的联合使用有效逆转了HNSCC特异性免疫耐药性，是克服对ICB治疗耐药性的一种有前景的策略。
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.