Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization
Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization
复制标题
抑制 xCT 通过外泌体 PD-L1 诱导巨噬细胞 M2 极化抑制抗 PD-1/L1 黑色素瘤治疗的功效
DOI：
10.1016/j.ymthe.2021.03.013
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发表时间：
2021-07-07
影响因子：
12.4
通讯作者：
Peng, Cong
中科院分区：
文献类型：
--
作者：
Liu, Nian;Zhang, JiangLin;Peng, Cong
肿瘤细胞通过胱氨酸/谷氨酸转运蛋白胱氨酸-谷氨酸交换（xCT）增加谷氨酸释放，以平衡肿瘤细胞中的氧化稳态并促进肿瘤进展。尽管临床研究已经显示了在黑色素瘤中靶向程序性细胞死亡1（PD-1）/程序性死亡配体1（PD-L1）信号传导的潜力，但应答率较低。然而，目前尚不清楚谷氨酸代谢如何影响黑色素瘤中的抗PD-1/PD-L1治疗功效。在这里，我们证明，虽然通过药理学抑制剂抑制xCT，（柳氮磺胺吡啶[SAS]），经美国食品和药物管理局（FDA）批准用于炎症性疾病，或黑色素瘤细胞中基因敲除诱导的活性氧簇（ROS）相关死亡，xCT的抑制通过上调PD-1/PD-L1免疫检查点阻断显著降低了抗PD-1/PD-L1免疫检查点阻断的功效。因此，携带从黑素瘤细胞分泌的相对大量的PD-L1的外泌体导致M2巨噬细胞极化并降低抗PD-1/PD-L1疗法在黑素瘤中的功效。总之，我们的结果表明，SAS抑制xCT是一种有前途的黑色素瘤治疗策略;另一方面，SAS治疗通过外泌体PD-L1诱导的巨噬细胞M2极化减弱了抗PD-1/PD-L1的疗效，并最终诱导抗PD-1/PD-L1治疗抗性。
Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.