がん免疫療法における免疫関連有害事象発症のメカニズム解明
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 |
Section | 一般 |
Review Section |
Basic Section 53030:Respiratory medicine-related
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Research Institution | Nagoya University |
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 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2022)
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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 |
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 MHC-KO mice (A24-Tg mice) as a model. We have confirmed that the 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
2: Research has progressed on the whole more than it was originally planned.
Reason
The objective of the second year (2022-2023) was successfully completed by the generation of the homozygous A24-Tg mice. We applied the previously developed protocol to induce CTLs against a model peptide antigen (ovalbumin) in the homozygous A24-Tg mice setting. We were able to show that ovalbumin peptides can be presented in HLA-A24-restricted manner in our homozygous A24-Tg animals confirming the feasibility of the immunization approach to induce and assay the peptide/MHC-restricted cytotoxic T cells (CTLs) using ELISpot. However, induction of self-reacting CTLs using immunization with self-GPRC5A peptide still remains a challenge.
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Strategy for Future Research Activity |
Currently we are trying to immunize homozygous A24-Tg mice treated with ICIs to mimic patients' treatment conditions. We are using murine GPRC5A synthetic peptide in conjunction with the Freund's adjuvant for immunization along with anti-PD-1 Ab injections. We may use another adjuvant setting if induction of self-reacting CTLs using current protocol doesn’t show significant progress. Upon induction of self-reactive cellular immune response in HLA-A24-Tg MHC-KO mice we are going to probe whether such induced CTLs attack HLA-A24-expressing lung tissue causing inflammation and damage similar to irAEs in patients.
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Report
(2 results)
Research Products
(2 results)