Papers

Peer-reviewed Last author Corresponding author International journal
Sep, 2021

Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes

Journal for ImmunoTherapy of Cancer
  • Mikako Nishida
  • Nahoko Yamashita
  • Taisaku Ogawa
  • Keita Koseki
  • Eiji Warabi
  • Tomoyuki Ohue
  • Masaaki Komatsu
  • Hirokazu Matsushita
  • Kazuhiro Kakimi
  • Eiryo Kawakami
  • Katsuyuki Shiroguchi
  • Heiichiro Udono
  • Display all

Volume
9
Number
9
First page
e002954
Last page
e002954
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1136/jitc-2021-002954
Publisher
BMJ

<sec><title>Background</title>Metformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.

</sec><sec><title>Methods</title>MitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.

</sec><sec><title>Results</title>Met administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.

</sec><sec><title>Conclusions</title>We found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.

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Link information
DOI
https://doi.org/10.1136/jitc-2021-002954
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34531248
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449974
URL
https://syndication.highwire.org/content/doi/10.1136/jitc-2021-002954
ID information
  • DOI : 10.1136/jitc-2021-002954
  • eISSN : 2051-1426
  • Pubmed ID : 34531248
  • Pubmed Central ID : PMC8449974

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