2. Academic Validation
  3. 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

  • Mol Ther. 2021 Jul 7;29(7):2321-2334. doi: 10.1016/j.ymthe.2021.03.013.
Nian Liu 1,  JiangLin Zhang 1,  Mingzhu Yin 1,  Hong Liu 1,  Xu Zhang 1,  Jiaoduan Li 1,  Bei Yan 1,  Yeye Guo 1,  Jianda Zhou 2,  Juan Tao 3,  Shuo Hu 4,  Xiang Chen 5,  Cong Peng 6
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan 410000, China; Human Engineering Research Center of Skin Health and Disease, Changsha, Hunan 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410000, China.
  • 2 Department of Plastic Surgery of Third Xiangya Hospital, Central South University, Changsha 410000, China.
  • 3 Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
  • 4 Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China.
  • 5 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan 410000, China; Human Engineering Research Center of Skin Health and Disease, Changsha, Hunan 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410000, China. Electronic address: chenxiangck@126.com.
  • 6 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan 410000, China; Human Engineering Research Center of Skin Health and Disease, Changsha, Hunan 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410000, China. Electronic address: pengcongxy@csu.edu.cn.
PMID: 33744468 DOI: 10.1016/j.ymthe.2021.03.013
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.

Keywords

PD-1/PD-L1; exosome; macrophages; melanoma; xCT.

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