| Project/Area Number |
21K08152
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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 53030:Respiratory medicine-related
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| Research Institution | Nagoya University |
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Principal Investigator |
コーチン ビタリー 名古屋大学, 医学系研究科, 特任助教 (30648001)
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| Project Period (FY) |
2021-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | GPRC5A / irAEs / ICIs / autoimmune Ab / cytotoxic T cells / irAEs, / Autoimmune antibody / Cytotoxic T cells / Lung-related irAEs / Immune checkpoint |
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| Outline of Research at the Start |
We are trying to elucidate the mechanisms that drive the immune-mediated recognition and killing of cancer cells as well as autoimmune damage to normal/healthy cells (immune-related adverse events, irAEs) by cytotoxic T lymphocytes activated upon immune checkpoint inhibitor (ICI) therapy. Understanding the mechanisms that underlie the development of the irAE-based autoimmune lung damage in ICI-treated patients will shed light on the ways to improve immunotherapy efficiency and for better managing of irAEs.
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| Outline of Annual Research Achievements |
Immune Related Adverse Events (irAEs) restrain ICIs use. The irAEs are caused by ICI-induced autoimmunity against self-tissues by auto-antibody (Ab) or self-reacting T cells. We found GPRC5A-derived peptide epitope presented by HLA-A24 specifically in human lung cells and currently investigating whether autoreactive T cells and/or Ab to GPRC5A may be responsible for the inflammation and damage in lung tissue of patients who underwent treatment with ICIs.
We use HLA-A24-transgenic mice (A24-Tg) as a model. We have confirmed that lung tissue of the A24-Tg animals express HLA-A24 and can process and present GPRC5A-derived peptide epitope identical to the one in human cells.
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
The objective of the third year (2023-2024) was completed by numerous attempts to induce self-reacting CTLs using immunization of homozygous A24-Tg mice with mouse self-GPRC5A peptide. We used a number of protocols that varied in immunization intervals (ranging from 10 to 20 days), different combination of ICI antibody (and-PD-1 and/or anti-CTLA-4), and age of mice (young vs. old). We observed a tendency for a higher number of immune cell infiltrates (so called LNLS, lymph node-like structures) in the H/E-stained FFPE lung tissue specimens of mice immunized and treated with and-PD-1 and -CTLA-4 Ab. However, we couldn’t isolate self-reacting CTLs using these immunization schemes.
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| Strategy for Future Research Activity |
It seems that congenic expression of GPRC5A in mice precludes induction of self-reacting CTLs as they are removed during negative selection process in thymus. We are currently developing GPRC5A knock-out (KO) / A24-Tg mice to address this issue by using CRISPR gene editing. Such GPRC5A-KO/A24-Tg mice should have intact precursor CD8+ CTLs directed against the GPRC5A epitope. Theoretically such CTLs could be easily induced upon immunization. Upon their induction, they can be expanded and adoptively transferred to A24-Tg mice with intact (wild type) GPRC5A gene, thus turning into self-reactive CTLs. We will investigate whether these CTLs would attack HLA-A24-expressing lung tissue causing inflammation and damage similar to irAEs in patients.
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