Natural Killer (NK) Cell Immunotherapy Towards Adult T Cell Leukemia (ATL) via Exaltation of MICA/B Expression and Augments NK Cytotoxicity

我们检查了各种ATL细胞系（艾德-、TL-Om 1、S1 T、KK-1、LMHW 5、OATL-4和SU 9 T1）上的云母/B表达。我们发现艾德-和TL-Om 1在细胞表面上高云母/B，而S1 T细胞显示非常低/无云母/B表达。我们使用艾德-、TL-Om 1作为代表性云母/Bhigh ATL，使用S1 T作为云母/Bno ATL。然后，我们测试了S1 T、艾德-和TL-Om 1的NK细胞毒性，发现具有非常低的云母/B表达的S1 T细胞抵抗NK细胞毒性，而艾德-和TL-Om 1对NK细胞毒性敏感。结果表明，云母/B，这是NKG 2D配体是至关重要的NK细胞的细胞毒性。我们证明iMID增加ATL上的云母/B表达。我们测试了iMID治疗对云母/B表达的功效。在本研究中检测了来那度胺、泊马度胺、伊贝度胺、CC-92480。用ATL测试非细胞毒性剂量。在所有这些中，CC-92480显示最高的增强云母/B表达的功效。通过使用来自健康供体的原代NK细胞，我们发现来那度胺、泊马度胺、伊贝度胺和CC-92480使ATL对NK细胞毒性敏感，并且CC-92480在iMID中显示最高功效。

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.