2021 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
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2021-04-01 – 2024-03-31
|
| Keywords | GPRC5A / irAEs / ICIs / Autoimmune antibody / Cytotoxic T cells |
|---|
| Outline of Annual Research Achievements |
Immune Related Adverse Events (irAEs) restrain ICIs use. The irAEs are caused by ICI-induced autoimmune reaction against self-tissues by self-directed antibody (Ab) and/or autoimmune T cells. We found GPRC5A-derived peptide epitope presented by HLA-A24 specifically in lung 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 that underwent treatment with ICI.
We used plasma samples from patients who developed irAEs in lung (IP) (30) and those who didn’t(36). Samples from healthy donors(30) were used as controls.
Average level of anti-GPRC5A Ab by ELISA in patients was significantly higher than the Ab level in controls. Patients with irAEs had slightly higher Ab level than those without.
|
| 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 first year (2021-2022) was successfully completed by the optimization of the anti-GPRC5A Ab assay method (ELISA) as well as a pilot screening of a limited number of patients plasma samples that developed/didn't develop irAEs upon ICI treatment.
We have optimized the immunization protocol to induce and assay the peptide/MHC-restricted cytotoxic T cells (CTLs) using ELISpot. We are going to apply the method to induce CTLs directed against GPRC5A self-peptide presented in HLA-A24-restricted manner in HLA-A24 transgenic (Tg) MHC-KO mice. Breeding of the HLA-A24-Tg MHC-KO mice for the experiments is a rather laborious and time-consuming process.
|
| Strategy for Future Research Activity |
We are going to increase the number of patients plasma samples to confidently verify whether the anti-GPRC5A Ab level would be associated with irAEs in lung tissue.
We are going to use GPRC5A synthetic peptide in conjunction with the Freund's adjuvant to immunize HLA-A24-Tg MHC-KO mice treated with ICIs to mimic patients treatment conditions. Amino acid sequence of the GPRC5A epitope presented by HLA-A24 in humans is conserved in its murine homolog. Therefore upon induction of self-reactive cellular immune response in HLA-A24-Tg MHC-KO mice we are going to probe whether such induced CTLs would attack HLA-A24-expressing lung tissue causing inflammation and damage similar to irAEs.
|
| Causes of Carryover |
Several mass spectrometry experiments were planned this fiscal year. However, establishing primary cancer cell lines to be used for the analyses took longer than expected. Therefore some mass spectrometry experiments were postponed to the next fiscal year. Breeding of the HLA-A24-Tg MHC-knockout mice seems to take longer compared to WT animals. They did not expand to enough numbers this year. Therefore, I postponed some immunization experiments to the next fiscal year.
|
