2. Academic Validation
  3. Eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5 mediated M1 macrophage polarization in melanoma

Eravacycline improves the efficacy of anti-PD1 immunotherapy via AP1/CCL5 mediated M1 macrophage polarization in melanoma

  • Biomaterials. 2024 Sep 11:314:122815. doi: 10.1016/j.biomaterials.2024.122815.
Nian Liu 1,  Mingjie Yan 1,  Can Lu 1,  Qian Tao 1,  Jie Wu 1,  Zhaokai Zhou 2,  Jing Chen 3,  Xiang Chen 4,  Cong Peng 5
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Human Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Furong Laboratory, Central South University, Changsha, Hunan, 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
  • 2 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Henan, 450052, China.
  • 3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
  • 4 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Human Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Furong Laboratory, Central South University, Changsha, Hunan, 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China. Electronic address: chenxiangck@126.com.
  • 5 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Human Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; Furong Laboratory, Central South University, Changsha, Hunan, 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China. Electronic address: pengcongxy@csu.edu.cn.
PMID: 39288620 DOI: 10.1016/j.biomaterials.2024.122815
Abstract

Screening approved library is a promising and safe strategy to overcome the limitation of low response rate and drug resistance in immunotherapy. Accumulating evidence showed that the application of Antibiotics has been considered to reduce the effectiveness of anti-PD1 immunotherapy in tumor treatment, however, in this study, an Antibiotic drug (Eravacycline, ERV) was identified to improve the efficacy of anti-PD1 immunotherapy in melanoma through screening approved library. Administration of ERV significantly attenuated melanoma cells growth as well as directly or indirectly benefited M1 macrophage polarization. Meanwhile, ERV treatment significantly induced cellular Autophagy via damage of mitochondria, leading to up-regulation of ROS production, subsequently, raised CCL5 secretion through elevation AP1 binding to CCL5 promoter via p38 or JNK1/2 activation. Knockdown of Ccl5 expression attenuated ERV triggered M1 macrophage polarization in melanoma cells. Clinical analysis revealed a positive association between high expression of CCL5 and improved prognosis as well as a favorable anti-PD1 therapy in melanoma patients. As expected, application of ERV improved the efficacy of anti-PD1. Overall, our results approved that ERV enhances the efficacy of anti-PD1 immunotherapy in melanoma by promoting the polarization of M1 macrophages, which provided novel therapeutic strategy for improving the effectiveness of melanoma anti-PD1 immunotherapy.

Keywords

Anti-PD1 immunotherapy; CCL5; Eravacycline; M1 macrophage; Melanoma.

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