MYC regulates the antitumor immune response through CD47 and PD-L1.
MYC regulates the antitumor immune response through CD47 and PD-L1.
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DOI：
10.1126/science.aac9935
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发表时间：
2016-04-08
期刊：
影响因子：
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通讯作者：
Felsher DW
中科院分区：
文献类型：
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作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
MYC癌基因编码在许多人类癌症中过表达的转录因子。在这里，我们表明MYC调节肿瘤细胞表面两种免疫检查点蛋白的表达，先天免疫调节因子CD 47（分化簇47）和适应性免疫检查点PD-L1（程序性死亡配体1）。抑制小鼠肿瘤和人类肿瘤细胞中的MYC导致CD 47和PD-L1 mRNA和蛋白水平降低。发现MYC直接与CD 47和PD-L1基因的启动子结合。MYC在小鼠肿瘤中的失活下调了CD 47和PD-L1的表达，并增强了抗肿瘤免疫应答。相反，当MYC在CD 47或PD-L1表达增强的肿瘤中失活时，免疫反应受到抑制，肿瘤继续生长。因此，MYC似乎部分通过调节免疫调节分子来启动和维持肿瘤发生。
The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface, the innate immune regulator, CD47 (Cluster of Differentiation 47) and the adaptive immune checkpoint, PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 mRNA and protein. MYC was found to bind directly to the promoters of the CD47 and PD-L1 genes. MYC inactivation in mouse tumors downregulated CD47 and PD-L1 expression and enhanced the anti-tumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed and tumors continued to grow. Thus MYC appears to initiate and maintain tumorigenesis in part through the modulation of immune regulatory molecules.