Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma
Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma
复制标题
瑞戈非尼通过抑制黑色素瘤中 PD-L1 和 IDO1 的表达来促进抗肿瘤免疫
DOI：
10.1158/1078-0432.ccr-18-2840
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发表时间：
2019-07-15
影响因子：
11.5
通讯作者：
Zhu，Xiao-Feng
中科院分区：
文献类型：
--
作者：
Wu，Rui-Yan;Kong，Peng-Fei;Zhu，Xiao-Feng
目的：免疫检查点阻断（ICB）治疗在少数癌症患者中诱导持久的肿瘤消退。在这项研究中，我们的目的是确定激酶抑制剂，能够增加抗黑色素瘤免疫。实验设计：进行基于流式细胞术的筛选以鉴定可阻断IFNγ诱导的黑素瘤细胞中PD-L1表达的激酶抑制剂。测定了瑞戈非尼单独或与免疫疗法联合的体外和体内药理学活性。使用基因表达Omnibus（GEO）和癌症基因组图谱（TCGA）数据集，在接受或不接受抗PD-1治疗的黑色素瘤患者中探索和分析了瑞戈非尼的机制。结果如下：通过对激酶抑制剂库的筛选，我们发现了大约20种药物可使细胞表面PD-L1水平降低一半以上，而瑞戈非尼是最有效的药物之一。此外，我们的研究结果表明，在体外和体内，瑞格非尼，强烈促进抗肿瘤疗效时，与IFNγ或ICB。通过靶向RET-Src轴，瑞戈非尼有效抑制JAK 1/2-STAT 1和MAPK信号传导，随后减弱IFNγ诱导的PD-L1和IDO 1表达，而不显著影响MHC-I表达。RET和Src共同高表达是黑色素瘤患者ICB与否的独立预后不良因素，可能通过抑制抗肿瘤免疫应答而发挥作用。结论：我们的数据揭示了减轻IFNγ诱导的PD-L1和IDO 1表达的新机制，并为临床上探索ICB与瑞格非尼的新组合提供了理论基础，特别是在RET/Src轴激活的黑色素瘤中。
Purpose: Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity. Experimental Design: Flow cytometry–based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti–PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. Results: Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET–Src axis, regorafenib potently inhibited JAK1/2–STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response. Conclusions: Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.