| Project/Area Number |
23K14554
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
呉 智聞 東京大学, 定量生命科学研究所, 特任研究員 (80883983)
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| Project Period (FY) |
2023-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2024: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | CD83 / Tpex / CAR-T / immunotherapy / T cell exhaustion |
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| Outline of Research at the Start |
T cells are a major population to eliminate tumor cells. But, exhausted T cells are attenuated for proliferation and cytotoxicity . Only progenitor exhausted T cells can be reinvigorated by anti-PD1 blockade. This research is to seek surface molecules that identify progenitor exhausted T cells.
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| Outline of Annual Research Achievements |
Among exhausted T cells are precursor exhausted T cells (TPEX), a subset retaining proliferative capacity. While functionally distinct and crucial for antitumor immunity, TPEX shares some phenotypic traits with other T-cell subsets in tumor-infiltrating T-lymphocytes (TIL).
Here, we investigate TPEX-specific surface markers using chimeric antigen receptor (CAR)-engineered T cell-treated tumor models. Our findings reveal predominant CD83 expression in CCR7+PD1+ intratumoral CAR-T cells, compared to CCR7-PD1+ and CAR-negative T cells. CD83+CCR7+ CAR-T cells demonstrate enhanced antigen-induced proliferation and IL-2 production over CD83- T cells. Additionally, we confirm CD83 selective expression in CCR7+PD1+ T cells in primary TIL samples.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
We have finished all planned projects and experiments.
We assessed the phenotypic and functional properties of the exhausted antitumor T cells in an experimental model. We identified robust markers that were preferentially expressed in the TPEX. We extracted six surface molecule-encoding genes by using publicly available gene expression data. T cells double positive for CD83 and CCR7 possess functional properties of precursor exhausted T cells. We confirmed CD83 is induced upon T cell activation and its overexpression limits effector T cell functions. We also found CD83 is predominantly expressed in naturally occurring TILs with a precursor phenotype.
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| Strategy for Future Research Activity |
Since CD83 has been identified as a selective expression marker in CCR7+PD1+ T cells in primary TIL samples, it might be considered a prognostic marker for predicting clinical outcomes in ICB therapy. However, the specific ligand for CD83 has not yet been confirmed. Previous studies investigating the effect of CD83 ligation on conventional T cells have been controversial. While membranous CD83 expression in dendritic cells promotes T-cell expansion and effector functions, a soluble form of CD83 inhibits T cell proliferation. These apparently discrepant results may suggest that the optimal strength of CD83 exists for efficient T cell expansion. Our further study will focus on predicting ICB therapy outcomes based on CD83 expression and also aim to identify its ligands.
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