2. Academic Validation
  3. Metformin-induced reduction of CCR8 enhances the anti-tumor immune response of PD-1 immunotherapy in glioblastoma

Metformin-induced reduction of CCR8 enhances the anti-tumor immune response of PD-1 immunotherapy in glioblastoma

  • Eur J Pharmacol. 2023 Dec 22:176274. doi: 10.1016/j.ejphar.2023.176274.
Yanyan Li 1,  Bin Liu 2,  Yufei Cao 3,  Lize Cai 1,  Youxin Zhou 1,  Wei Yang 4,  Ting Sun 5
Affiliations

Affiliations

  • 1 Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 2 Department of Neurosurgery, Qinghai Provincial People's Hospital, Xining, Qinghai, China.
  • 3 Department of Critical Care Medicine, Affiliated First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 5 Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: [email protected].
PMID: 38142852 DOI: 10.1016/j.ejphar.2023.176274
Abstract

Immunotherapy strategies targeting the programmed cell death 1 (PD-1) in clinical treatments have shown limited success in controlling glioblastoma malignancies. Metformin exserts antitumor function, yet the underlying mechanisms remain unclear. Here, we investigated whether metformin could enhance the effectiveness of anti-PD-1 therapy by activating the immune system. Whether combination of an anti-PD-1 antibody or not, metformin significantly increased tumor-infiltrating CD4+ T cells while decreased regulatory T (Treg) cells in a mouse GBM model. Additionally, metformin reduced CC motif Chemokine Receptor CCR8 and elevated Interleukin 17 A (IL-17 A) expressions. Mechanistically, metformin reduces histone acetylation at the CCR8 promotor and inhibits CCR8 expression by upregulating AMP-activated protein kinase (AMPK)-activated Sirtuin 2 (SIRT2). Metformin enhances the effectiveness of anti-PD-1 immunotherapy by reducing CCR8 expression on tumor-infiltrating Treg cells, suggesting that metformin has an antitumor effect by alleviating immunosuppression and promoting T cell-mediated immune response.

Keywords

AMPK; CCR8; Metformin; SIRT2; Treg.

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