2021 Fiscal Year Annual Research Report
Mechanistic analysis of the PD-1 blockade combination cancer immunotherapy with BTK inhibitors.
| Project/Area Number |
21F20405
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| Research Institution | Kyoto University |
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Principal Investigator |
本庶 佑 京都大学, 医学研究科, 特任教授 (80090504)
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| Co-Investigator(Kenkyū-buntansha) |
ZOU YIXIN 京都大学, 医学研究科, 外国人特別研究員
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| Project Period (FY) |
2021-04-28 – 2023-03-31
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| Keywords | BTK inhibitor / PD-1 blockade therapy / combination therapy |
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| Outline of Annual Research Achievements |
Previous articles reported that ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could enhance the efficacy of PD-1 blockade therapy, however, the mechanisms remained unclear. In this project, we chose ibrutinib and the second-generation BTK inhibitor, acalabrutinib, as the candidate drugs. Besides BTK, ibrutinib can also target other kinases like IL2-inducible T-cell kinase, while acalabrutinib is highly selective BTK inhibitor. We selected colon adenocarcinoma cell MC38 (PD-1 therapy responsive) and colon carcinoma cell CT26 (PD-1 therapy unresponsive) for further research. For MC38 mouse model, acalabrutinib could enhance the efficacy of PD-1 blockade therapy, while ibrutinib failed. Neither of them showed better efficacy in CT26 model.
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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
Under the support of Kakenhi and under the supervision of Prof. Honjo, we have almost finished Research Plan for FY2021 and received the following achievements:
1. Chose suitable BTK inhibitors for research.
2. Chose suitable cell lines for research.
3. Checked the efficacy of combination therapy in mouse model and found that acalabrutinib could enhance the efficacy of PD-1 blockade therapy in MC38 model, while ibrutinib failed, which might be due to different selectivity for BTK and other kinases. For PD-1 therapy unresponsive cell line CT26, BTK inhibitors had no effect on PD-1 blockade therapy.
4. In addition to metabolism, we also guessed that BTK inhibitors were associated with endoplasmic reticulum stress.
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| Strategy for Future Research Activity |
CD8+ T cells in DLNs and tumor will be analyzed after combination therapy, including mitochondrial metabolism analysis and glycolysis analysis. The proliferation, survival, apoptotic cell numbers and metabolic changes of naive, effector and memory CD8+ T cells will be assessed. After establishing these evaluating assays in vitro, we will screen several chemical reagents which can enhance the efficacy of PD-1 blockade by changing metabolic pattern.
In addition to metabolism, we think that endoplasmic reticulum (ER) stress is an important part in this experiment. We will check the expression of ER stress-related genes, monitor changes in the ER redox state, measure calcium distribution and assess ER structure and functions to reflect ER stress.
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