Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization
Nian Liu, JiangLin Zhang, Mingzhu Yin, Hong Liu, Xu Zhang, Jiaoduan Li, Bei Yan, Yeye Guo, Jianda Zhou, Juan Tao, Shuo Hu, Xiang Chen, Cong Peng, Nian Liu, JiangLin Zhang, Mingzhu Yin, Hong Liu, Xu Zhang, Jiaoduan Li, Bei Yan, Yeye Guo, Jianda Zhou, Juan Tao, Shuo Hu, Xiang Chen, Cong Peng
Abstract
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.
Trial registration: ClinicalTrials.gov NCT04205357.
Keywords: PD-1/PD-L1; exosome; macrophages; melanoma; xCT.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
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Source: PubMed