Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 5, Pages E761-E770Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620433114
Keywords
PD-1; cancer immunotherapy; mitochondria; immune metabolism; PGC-1 alpha
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Funding
- Japan Agency for Medical Research and Development of Japan (AMED) [145208, 16770835]
- Tang Prize Foundation
- Cell Science Foundation
- Tokyo Biochemical Research Foundation
- AMED-CREST (AMED Grant) [14532135]
- [16748159]
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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 1 alpha (PGC-1a alpha) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1 alpha 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.
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