Human Ovarian Tumor Cells Escape γδ T Cell Recognition Partly by Down Regulating Surface Expression of MICA and Limiting Cell Cycle Related Molecules

BackgroundMechanisms of human Vγ2Vδ2 T cell-mediated tumor immunity have yet to be fully elucidated.
Methods and FindingsAt least some tumor cell recognition is mediated by NKG2D-MICA interactions. Herein, by using MTT assay and PI-BrdU co-staining and Western-blot, we show that these Vγ2Vδ2 T cells can limit the proliferation of ovarian tumor cells by down regulation of apoptosis and cell cycle related molecules in tumor cells. Cell-to-cell contact is critical. γδ T cell-resistant, but not susceptible ovarian tumor cells escape γδ T cell-mediated immune recognition by up-regulating pErk1/2, thereby decreasing surface MICA levels. Erk1/2 inhibitor pretreatment or incubation prevents this MICA decrease, while up-regulating key cell cycle related molecules such as CDK2, CDK4 and Cyclin D1, as well as apoptosis related molecules making resistant tumor cells now vulnerable to γδ T cell-mediated lysis.
ConclusionThese findings demonstrate novel effects of γδT cells on ovarian tumor cells.

背景 人类Vγ2Vδ2 T细胞（Vγ2Vδ2 T cell）介导的肿瘤免疫机制尚未完全阐明。方法与研究结果 至少部分肿瘤细胞识别过程由NKG2D-MICA相互作用介导。本研究采用MTT实验（MTT assay）、PI-BrdU双染色（碘化丙啶-溴脱氧尿苷双染色）及蛋白质印迹（Western-blot）技术，证实此类Vγ2Vδ2 T细胞可通过下调肿瘤细胞内的凋亡与细胞周期相关分子，抑制卵巢肿瘤细胞的增殖，且细胞间接触是该调控过程的关键。对γδ T细胞产生抗性而非敏感性的卵巢肿瘤细胞，可通过上调磷酸化细胞外调节蛋白激酶1/2（pErk1/2）的表达，降低表面MICA分子水平，从而逃逸γδ T细胞介导的免疫识别。使用Erk1/2抑制剂预处理或共孵育可阻断该MICA分子的下调过程，同时上调关键细胞周期相关分子如细胞周期蛋白依赖性激酶2（CDK2）、细胞周期蛋白依赖性激酶4（CDK4）及细胞周期蛋白D1（Cyclin D1），并上调凋亡相关分子，使原本具有抗性的肿瘤细胞重新对γδ T细胞介导的细胞裂解作用敏感。结论 本研究结果揭示了γδ T细胞对卵巢肿瘤细胞的全新生物学作用。