| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
|---|
| Outline of Annual Research Achievements |
MICA/B expression on various ATL cell lines (ED-, TL-Om1, S1T, KK-1, LMHW5, OATL-4, and SU9T1). ED- and TL-Om1 express high MICA/B on cell surface whereas S1T cell shows very low/no MICA/B expression. We tested S1T, ED-, and TL-Om1 for NK cytotoxicity and found that S1T cells which have very low MICA/B expression, resist to NK cell cytotoxicity whereas ED-, and TL-Om1 are sensitive to NK cytotoxicity. The results suggest that MICA/B, which is NKG2D ligand is crucial for NK cell cytotoxicity.
We then used sodium butyrate (NaBu) to increase MICA/B expression on ATL. We found 1 mM NaBu upregulated MICA/B expression on ED-, and TL-Om1 cells. However, S1T cells, which have very low MICA/B expression, does not respond to any MICA/B enhancing agent. Based on our killing assay, NaBu enhanced MICA/B expression on ED- and TL-Om1 cells, and increased NK cytotoxicity compared to non-treated ATL. The results correlate both NK cell line and primary NK cells from healthy donor. MICA/B shedding was negative with non-relevant to NK cytotoxicity.
We demonstrate iMIDs increase MICA/B expression on ATL. We tested the efficacy of iMIDs treatment for MICA/B expression. Lenalidomide, Pomalidomide, Iberdomide, CC-92480 were tested in this study. The noncytotoxic doses were tested with ATL. Among all of those, CC-92480 show highest efficacy to enhance MICA/B expression. By using primary NK cells from healthy donor, we found that Lenalidomide, Pomalidomide, Iberdomide and CC-92480 sensitized ATL to NK cytotoxicity and CC-92480 displayed the highest efficacy among iMIDs.
|
| Strategy for Future Research Activity |
We are working on the process of MICA/B overexpression on S1T and knockdown MICA/B on ED- cells and tested to confirm MICA/B is crucial for NK sensitization. Finally, we will use ATL- bearing immunodeficient mice to study NK cell adoptive transfer and tumor control. We will test different ATLs that have different level of MICA/B expression and observe the correlation of MICA/Bhigh or MICA/Blow and tumor burden after NK adoptive transfer. In addition, we will wrap up all experiments as well as planing to write manuscript and further submit to immunology field journal.
|
