Journal
CANCER CELL
Volume 40, Issue 2, Pages 201-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2022.01.001
Keywords
-
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17H06162]
- Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan [16K15551]
- C grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan [21K07252]
- JSPS KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan [16H06279]
- JSPS Research Fellowship from the Ministry of Education, Culture, Sports, Science and Technology of Japan [202101784]
- Projects for Cancer Research by Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED) [16cm0106301h0001, 19cm0106335h0002]
- Development of Technology for Patient Stratification Biomarker Discovery grant from the Japan Agency for Medical Research and Development (AMED) [19ae0101074s0401]
- National Cancer Center Research and Development Fund [28-A-7, 31-A-7]
- Research Grant of the Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- Mochida Memorial Foundation
- Daiichi Sankyo Foundation
- Kowa Life Science Foundation
- MSD Life Science Foundation
- SGH Foundation
- Ichiro Kanehara Foundation
- Yasuda Medical Foundation
- Suzuken Memorial Foundation
- Daiwa Securities Health Foundation
- Japan Research Foundation for Clinical Pharmacology
- Japanese Foundation for Multidisciplinary Treatment of Cancer
- Yokoyama Foundation For Clinical Pharmacology
- Japan Cancer Society
- Princess Takamatsu Cancer Research Fundation
- Hitachi Global Foundation
- Ono Pharmaceutical
- Grants-in-Aid for Scientific Research [21K07252, 16K15551] Funding Source: KAKEN
Ask authors/readers for more resources
In highly glycolytic tumors, regulatory T (Treg) cells have higher PD-1 expression compared to effector T cells. Under low-glucose conditions, Treg cells actively absorb lactic acid through monocarboxylate transporter 1 (MCT1), promoting the expression of PD-1, while PD-1 expression by effector T cells is dampened. PD-1 blockade invigorates PD-1-expressing Treg cells, resulting in treatment failure.
The balance of programmed death-1 (PD-1)-expressing CD8(+) T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 trans location into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available