Carlsten Mattias, Namazi Ali, Reger Robert, Levy Emily, Berg Maria, St Hilaire Cynthia, Childs Richard W
Laboratory of Transplantation Immunotherapy, Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
Laboratory of Cardiovascular Regenerative Medicine, Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
Oncoimmunology. 2018 Nov 2;8(2):e1534664. doi: 10.1080/2162402X.2018.1534664. eCollection 2019.
Although the proteasome inhibitor bortezomib has significantly improved the survival of patients with multiple myeloma (MM), the disease remains fatal as most patients eventually develop progressive disease. Recent data indicate that MM cells can evade bortezomib-induced cell death by undergoing autophagy as a consequence of endoplasmatic reticulum (ER)-stress induced by proteasome inhibition. Here we show that bortezomib sensitizes MM cells to NK cell killing via two distinct mechanisms: a) upregulation of the TRAIL death receptor DR5 on the surface of MM cells and b) ER-stress induced reduction of cell surface HLA-E. The latter mechanism is completely novel and was found to be exclusively controlled by the inhibitory receptor NKG2A, with NKG2A single-positive (NKG2A) NK cells developing a selective augmentation in tumor killing as a consequence of bortezomib-induced loss of HLA-E on the non-apoptotic MM cells. In contrast, the expression of classical HLA class I molecules remained unchanged following bortezomib exposure, diminishing the augmentation of MM killing by NK cells expressing KIR. Further, we found that feeder cell-based expansion of NK cells increased both NK cell TRAIL surface expression and the percentage of NKG2A NK cells compared to unexpanded controls, substantially augmenting their capacity to kill bortezomib-treated MM cells. Based on these findings, we hypothesize that infusion of expanded NK cells following treatment with bortezomib could eradicate MM cells that would normally evade killing through proteasome inhibition alone, potentially improving long-term survival among MM patients.
尽管蛋白酶体抑制剂硼替佐米显著提高了多发性骨髓瘤（MM）患者的生存率，但该疾病仍然致命，因为大多数患者最终会发展为疾病进展。最近的数据表明，MM细胞可通过自噬逃避硼替佐米诱导的细胞死亡，这是蛋白酶体抑制诱导的内质网（ER）应激的结果。在此我们表明，硼替佐米通过两种不同机制使MM细胞对NK细胞杀伤敏感：a）MM细胞表面TRAIL死亡受体DR5上调；b）ER应激诱导细胞表面HLA-E减少。后一种机制是全新的，且发现完全由抑制性受体NKG2A控制，由于硼替佐米诱导非凋亡MM细胞上HLA-E缺失，NKG2A单阳性（NKG2A）NK细胞在肿瘤杀伤中出现选择性增强。相反，硼替佐米暴露后经典HLA I类分子的表达保持不变，这减少了表达KIR的NK细胞对MM杀伤的增强作用。此外，我们发现与未扩增的对照相比，基于饲养细胞的NK细胞扩增增加了NK细胞TRAIL表面表达和NKG2A NK细胞的百分比，显著增强了它们杀伤经硼替佐米处理的MM细胞的能力。基于这些发现，我们推测硼替佐米治疗后输注扩增的NK细胞可根除通常会通过单独蛋白酶体抑制逃避杀伤的MM细胞，这可能会提高MM患者的长期生存率。
