| Project/Area Number |
23K06603
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
TAKAHASHI LUCIA 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (60632982)
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2025: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2024: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | immune metabolites / immune regulation / PD-1 / biomarker / immune activation |
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| Outline of Research at the Start |
Using PD-1 knockout mouse as model, we aim to identify novel serum metabolites associated with immune activation and evaluate their immune regulatory properties. These compounds can be used as biomarkers for anti-PD-1 tumor therapy, and they can be targeted for the modulation of immune responses.
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| Outline of Annual Research Achievements |
In our preliminary studies of serum from immunodeficient mice, we found several compounds that are altered in the serum of PD-1 knockout mice when compared with wild type mice. We decided to focus on one compound, metabolite A, because it was also reported to be detected in higher levels in anti-PD-1 treatment responders comparing to non responders in PD-1 blockade cancer immunotherapy.
We speculate that compound A can be used as a marker of immune activation and it might play a role in modulating immune responses.
Metabolite A is reported to be produced in the liver and kidney, but we found that it is also produced and secreted by immune cells in vitro. Upon stimulation, mouse B cells and CD8+ T cells as well as human tonsil B cells produce and secrete compound A to culture media. Moreover, some tumor cell lines were also found to synthesize and secrete compound A in vitro. Strikingly, we found that neither the above mentioned immune cells nor the cancer cell lines express the key enzyme reported to be essential for the biosynthesis of compound A, suggesting that there should be a yet not described pathway responsible for its synthesis in immune cells.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The project is progressing smoothly.
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| Strategy for Future Research Activity |
We will search for enzymes that can be involved in compound A biosynthesis in immune cells. Also, as we think compound A can regulate immune responses, we will check the effect of compound A on cell cultures of different immune cells (B cells, T cells, macrophages, etc).
Moreover, because compound A was detected in higher levels in the serum of anti-PD-1 treatment responders comparing to non responders in PD-1 blockade cancer immunotherapy, we plan to evaluate the effect of compound A in mouse tumor models.
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