Affiliation:
1. Department of Inflammology, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-0041, Japan
2. Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan
3. Division of Nutriomics and Oncology, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan
Abstract
The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8
+
T cell–dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.
Funder
MEXT | Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
Takeda Science Foundation
Kowa Life Science Foundation
Foundation for Promotion of Cancer Research
Joint Research Program of the Institute for Genetic Medicine, Hokkaido University
Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University
Uehara Memorial Foundation
the UTEC-UTokyo FSI Research Grant Program
Publisher
Proceedings of the National Academy of Sciences
Cited by
5 articles.
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