2022 Fiscal Year Research-status Report
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 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 – 2024-03-31
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| Keywords | GPRC5A / irAEs, / ICIs / autoimmune Ab / cytotoxic T cells |
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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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| Causes of Carryover |
We performed additional breeding steps to establish homozygous A24-Tg mice line (instead of original heterozygous A24-Tg animals). Therefore, some mass spectrometry and immunization experiments were postponed to the following fiscal year.
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