PMID- 28096382
OWN - NLM
STAT- MEDLINE
DCOM- 20180412
LR  - 20211204
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 5
DP  - 2017 Jan 31
TI  - Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade 
      for T cell-dependent antitumor activity.
PG  - E761-E770
LID - 10.1073/pnas.1620433114 [doi]
AB  - 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 1alpha (PGC-1alpha) and T-bet. 
      Furthermore, direct activators of mTOR, AMPK, or PGC-1alpha 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.
FAU - Chamoto, Kenji
AU  - Chamoto K
AD  - Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto 
      University, Kyoto 606-8501, Japan.
FAU - Chowdhury, Partha S
AU  - Chowdhury PS
AD  - Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto 
      University, Kyoto 606-8501, Japan.
FAU - Kumar, Alok
AU  - Kumar A
AD  - Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto 
      University, Kyoto 606-8501, Japan.
FAU - Sonomura, Kazuhiro
AU  - Sonomura K
AD  - Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 
      606-8501, Japan.
AD  - Life Science Research Center, Technology Research Laboratory, Shimadzu 
      Corporation, Kyoto 604-8445, Japan.
FAU - Matsuda, Fumihiko
AU  - Matsuda F
AD  - Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 
      606-8501, Japan.
FAU - Fagarasan, Sidonia
AU  - Fagarasan S
AD  - Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN 
      Yokohama Institute, Yokohama 230-0045, Japan.
FAU - Honjo, Tasuku
AU  - Honjo T
AD  - Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto 
      University, Kyoto 606-8501, Japan; honjo@mfour.med.kyoto-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170117
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Cytokines)
RN  - 0 (Morpholines)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Pyrones)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Thiophenes)
RN  - 0 (Triazines)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - P68477CD2C 
      (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology/*therapeutic use
MH  - Biphenyl Compounds
MH  - Cell Line, Tumor
MH  - Cytokines/immunology
MH  - Lymph Nodes/immunology
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitochondria/drug effects/*metabolism
MH  - Morpholines/pharmacology/therapeutic use
MH  - Neoplasms/*drug therapy/immunology/metabolism
MH  - Oxygen Consumption
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
MH  - Programmed Cell Death 1 Receptor/*antagonists & 
      inhibitors/genetics/immunology/metabolism
MH  - Pyrones/pharmacology/therapeutic use
MH  - Reactive Oxygen Species/metabolism
MH  - T-Lymphocytes, Cytotoxic/*immunology/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Thiophenes/pharmacology/therapeutic use
MH  - Triazines/pharmacology/therapeutic use
PMC - PMC5293087
OTO - NOTNLM
OT  - PD-1
OT  - PGC-1alpha
OT  - cancer immunotherapy
OT  - immune metabolism
OT  - mitochondria
COIS- The authors declare no conflict of interest.
EDAT- 2017/01/18 06:00
MHDA- 2018/04/13 06:00
PMCR- 2017/01/17
CRDT- 2017/01/19 06:00
PHST- 2017/01/18 06:00 [pubmed]
PHST- 2018/04/13 06:00 [medline]
PHST- 2017/01/19 06:00 [entrez]
PHST- 2017/01/17 00:00 [pmc-release]
AID - 1620433114 [pii]
AID - 201620433 [pii]
AID - 10.1073/pnas.1620433114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E761-E770. doi: 
      10.1073/pnas.1620433114. Epub 2017 Jan 17.