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Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization.
Liu, Nian; Zhang, JiangLin; Yin, Mingzhu; Liu, Hong; Zhang, Xu; Li, Jiaoduan; Yan, Bei; Guo, Yeye; Zhou, Jianda; Tao, Juan; Hu, Shuo; Chen, Xiang; Peng, Cong.
Afiliação
  • Liu N; 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 Resea
  • Zhang J; 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 Resea
  • Yin M; 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 Resea
  • Liu H; 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 Resea
  • Zhang X; 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 Resea
  • Li J; 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 Resea
  • Yan B; 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 Resea
  • Guo Y; 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 Resea
  • Zhou J; Department of Plastic Surgery of Third Xiangya Hospital, Central South University, Changsha 410000, China.
  • Tao J; Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
  • Hu S; Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410000, China.
  • Chen X; 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 Resea
  • Peng C; 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 Resea
Mol Ther ; 29(7): 2321-2334, 2021 07 07.
Article em En | MEDLINE | ID: mdl-33744468
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema y/ de Transporte de Aminoácidos / Antígeno B7-H1 / Receptor de Morte Celular Programada 1 / Inibidores de Checkpoint Imunológico / Ativação de Macrófagos / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema y/ de Transporte de Aminoácidos / Antígeno B7-H1 / Receptor de Morte Celular Programada 1 / Inibidores de Checkpoint Imunológico / Ativação de Macrófagos / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article