Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2010 Feb 1;184(3):1139-42. doi: 10.4049/jimmunol.0902856. Epub 2009 Dec 21.
Bortezomib augments caspase-8 activity, rendering tumors susceptible to NK cell lysis. We hypothesized this effect would likewise sensitize tumors to Ag-specific CTLs. Instead, bortezomib-treated tumors that acquired sensitivity to NK cells simultaneously became resistant to killing by Ag-specific CTLs. Reduction in CTL killing persisted for days, was not due to changes in tumor expression of MHC class I, and was overcome by pulsing tumors with peptides recognized by tumor-reactive CTLs. Tumor-outgrowth experiments showed tumors grew faster in SCID mice when cocultures of tumor-reactive CTLs and bortezomib-treated tumors were injected compared with untreated tumors (tumor doubling time 3.1 and 10.6 d, respectively; p < 0.01), whereas tumors grew slower in mice receiving cocultures of NK cells and bortezomib-treated tumors compared with untreated tumors (11.8 d and 5.0 d, respectively; p < 0.01). These findings demonstrate bortezomib-treated tumors sensitized to NK cell apoptosis paradoxically acquire resistance to CTLs as a consequence of bortezomib altering proteasomal processing and presentation of tumor Ags.
硼替佐米增强了半胱天冬酶-8 的活性，使肿瘤容易被 NK 细胞溶解。我们假设这种效应同样会使肿瘤对 Ag 特异性 CTL 敏感。然而，硼替佐米处理后获得对 NK 细胞敏感性的肿瘤同时对 Ag 特异性 CTL 的杀伤产生了抗性。CTL 杀伤的减少持续了数天，并非由于肿瘤 MHC Ⅰ类表达的变化引起，并且通过用肿瘤反应性 CTL 识别的肽脉冲处理肿瘤而得到克服。肿瘤生长实验表明，与未处理的肿瘤相比，当将肿瘤反应性 CTL 和硼替佐米处理的肿瘤共培养物注入 SCID 小鼠时，肿瘤生长更快（肿瘤倍增时间分别为 3.1 和 10.6 天；p <0.01），而当将 NK 细胞和硼替佐米处理的肿瘤共培养物注入小鼠时，肿瘤生长较慢与未处理的肿瘤相比（分别为 11.8 天和 5.0 天；p <0.01）。这些发现表明，硼替佐米处理的肿瘤对 NK 细胞凋亡敏感，但由于硼替佐米改变了蛋白酶体加工和肿瘤 Ag 的呈递，因此对 CTL 产生了抗性。
