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

我们检测了不同的ATL细胞系(ED-、TL-OM1、S1T、KK-1、LMHW5、OATL-4和SU9T1)上MICA/B的表达。我们发现ED-OM1和TL-OM1在细胞表面高表达MICA/B，而S1T细胞低表达或不表达MICA/B。我们用ED-，TL-OM1作为代表性的MICA/BHIGH ATL，S1T作为MICA/BNO ATL。然后我们检测了S1T、ED-和TL-OM1对NK细胞的杀伤作用，发现MICA/B表达很低的S1T细胞对NK细胞的杀伤作用具有抵抗力，而ED-和TL-OM1对NK细胞的杀伤作用敏感。结果提示，MICA/B作为NKG2D配体在NK细胞杀伤中起着至关重要的作用。我们检测了IMIDs对MICA/B表达的影响。本研究对来那度胺、泊马度胺、伊贝多胺、CC-92480进行了试验。用ATL法检测非细胞毒性剂量。其中CC-92480对MICA/B基因表达的促进作用最强。使用健康供者的原代NK细胞，我们发现雷那度胺、泊马度胺、伊贝多胺和CC-92480增敏的ATL对NK细胞的杀伤作用最强，其中CC-92480的疗效最高。

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.