Natural Killer (NK) Cell Immunotherapy Towards Adult T Cell Leukemia (ATL) via Exaltation of MICA/B Expression and Augments NK Cytotoxicity
Project/Area Number |
22K16327
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | Kumamoto University |
Principal Investigator |
Panaampon Jutatip 熊本大学, ヒトレトロウイルス学共同研究センター, 客員助教 (60868313)
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Project Period (FY) |
2022-04-01 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2022)
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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)
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Keywords | ATL / iMIDs / NK sensitization / Adult T cell Leukemia / NK cells / MICA/MICB / NKG2D |
Outline of Research at the Start |
This study will elucidate the mechanism of ATL that enabling ATL to escape from NK immune surveillance. The study will also provide the promising immunotherapy for ATL treatment to stabilize the expression of NKG2DLs and to drive NK cell mediated ATL cytotoxicity. The research will be extended to prove mechanism in ATL xenograft mouse model by NK cell adoptive transfer.
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Outline of Annual Research Achievements |
We checked MICA/B expression on various ATL cell lines (ED-, TL-Om1, S1T, KK-1, LMHW5, OATL-4, and SU9T1). We found ED- and TL-Om1 express high MICA/B on cell surface whereas S1T cell shows very low/no MICA/B expression. We used ED-, TL-Om1 as representative MICA/Bhigh ATL and S1T as MICA/Bno ATL. We then test 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 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.
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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
We are doing 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. Moreover, we are working on more NK donors.
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Strategy for Future Research Activity |
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.
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Report
(1 results)
Research Products
(3 results)