Hallett William H D, Ames Erik, Motarjemi Milad, Barao Isabel, Shanker Anil, Tamang David L, Sayers Thomas J, Hudig Dorothy, Murphy William J
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada, Reno, NV 89557, USA.
J Immunol. 2008 Jan 1;180(1):163-70. doi: 10.4049/jimmunol.180.1.163.
Bortezomib is a proteasome inhibitor that has direct antitumor effects. We and others have previously demonstrated that bortezomib could also sensitize tumor cells to killing via the death ligand, TRAIL. NK cells represent a potent antitumor effector cell. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing. Preincubation of tumor cells with bortezomib had no effect on short-term NK cell killing or purified granule killing assays. Using a 24-h lysis assay, increases in tumor killing was only observed using perforin-deficient NK cells, and this increased killing was found to be dependent on both TRAIL and FasL, correlating with an increase in tumor Fas and DR5 expression. Long-term tumor outgrowth assays allowed for the detection of this increased tumor killing by activated NK cells following bortezomib treatment of the tumor. In a tumor purging assay, in which tumor:bone marrow cell mixtures were placed into lethally irradiated mice, only treatment of these mixtures with a combination of NK cells with bortezomib resulted in significant tumor-free survival of the recipients. These results demonstrate that bortezomib treatment can sensitize tumor cells to cellular effector pathways. These results suggest that the combination of proteasome inhibition with immune therapy may result in increased antitumor efficacy.
硼替佐米是一种具有直接抗肿瘤作用的蛋白酶体抑制剂。我们和其他人之前已经证明，硼替佐米还可以使肿瘤细胞对通过死亡配体TRAIL介导的杀伤敏感。自然杀伤细胞（NK细胞）是一种强大的抗肿瘤效应细胞。因此，我们研究了硼替佐米是否能使肿瘤细胞对NK细胞介导的杀伤敏感。用硼替佐米对肿瘤细胞进行预孵育，对短期NK细胞杀伤或纯化颗粒杀伤试验没有影响。使用24小时裂解试验，仅在使用穿孔素缺陷型NK细胞时观察到肿瘤杀伤增加，并且发现这种增加的杀伤依赖于TRAIL和FasL两者，这与肿瘤Fas和DR5表达的增加相关。长期肿瘤生长试验能够检测到硼替佐米处理肿瘤后活化的NK细胞对肿瘤杀伤的增加。在肿瘤清除试验中，将肿瘤：骨髓细胞混合物接种到接受致死性照射的小鼠体内，只有用NK细胞与硼替佐米联合处理这些混合物才能使受体小鼠显著无瘤存活。这些结果表明，硼替佐米治疗可使肿瘤细胞对细胞效应途径敏感。这些结果表明，蛋白酶体抑制与免疫治疗相结合可能会提高抗肿瘤疗效。
