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Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E761-E770. doi: 10.1073/pnas.1620433114. Epub 2017 Jan 17.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity.

Author information

1
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
2
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3
Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto 604-8445, Japan.
4
Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
5
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; honjo@mfour.med.kyoto-u.ac.jp.

Abstract

Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.

KEYWORDS:

PD-1; PGC-1α; cancer immunotherapy; immune metabolism; mitochondria

PMID:
28096382
PMCID:
PMC5293087
DOI:
10.1073/pnas.1620433114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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