LIN28/let-7/PD-L1 Pathway as a Target for Cancer Immunotherapy
LIN28/let-7/PD-L1 Pathway as a Target for Cancer Immunotherapy
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LIN28/let-7/PD-L1 通路作为癌症免疫治疗的靶点
DOI：
10.1158/2326-6066.cir-18-0331
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发表时间：
2019-03-01
影响因子：
10.1
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
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作者：
Chen, Yanlian;Xie, Chen;Zhao, Yong
PD-L1在癌症中的表达是通过LIN28/LET-7途径调节的，并使用小化合物LIN28-抑制物C1632来操纵。在体外和小鼠乳腺癌模型中，用这种化合物治疗可以提高抗肿瘤免疫力并抑制肿瘤细胞的生长。免疫检查点蛋白PD-1/PD-L1被认为是肿瘤免疫治疗的一个有前途的靶点。然而，使用抗体阻断PD-1和PD-L1之间的相互作用的客观应答率不到40%，并且PD-1/PD-L1表达的调节机制尚不清楚。在本研究中，我们鉴定了转录后抑制PD-L1表达的miRNA let-7。LIN28是一种在大多数癌细胞中上调的RNA结合蛋白，它抑制let-7的生物发生，从而促进PD-L1的表达。因此，抑制LIN28可能是防止癌细胞免疫逃避的一种策略。我们发现，用LIN28抑制剂C1632治疗，在体外和体内都能增加let-7和抑制PD-L1的表达，导致抗肿瘤免疫的重新激活。此外，C1632还显示出抑制小鼠癌细胞增殖和肿瘤生长的能力。总之，这些发现确定了LIN28/LET-7是PD-L1介导的免疫治疗的靶点，并揭示了C1632及其衍生物作为有前景的肿瘤治疗药物的潜力。
PD-L1 expression in cancers is regulated through the LIN28/let-7 pathway and manipulated using the small compound LIN28-inhibitor C1632. Treatment with this compound increases antitumor immunity and inhibits tumor cell growth in vitro and in a mouse breast cancer model. The immunocheckpoint protein PD-1/PD-L1 is considered a promising target for cancer immunotherapeutics. However, the objective response rate using antibodies that block the interaction between PD-1 and PD-L1 was less than 40%, and the mechanism underlying regulation of PD-1/PD-L1 expression is poorly understood. In this study, we identified the miRNA let-7 that posttranscriptionally suppresses PD-L1 expression. LIN28, an RNA binding protein upregulated in most cancer cells, inhibits the biogenesis of let-7, thus promoting PD-L1 expression. Therefore, inhibition of LIN28 may be a strategy to prevent immune evasion of cancer cells. We found that treatment with a LIN28 inhibitor, the small compound C1632, increases let-7 and suppresses PD-L1 expression, leading to reactivation of antitumor immunity in vitro and in vivo. In addition, C1632 also displayed the capacity to inhibit cancer cell proliferation and tumor growth in mice. Altogether, these findings identified LIN28/let-7 as a target for PD-L1–mediated immunotherapeutics and reveal the potential of C1632 and its derivatives as promising oncotherapeutic agents.