Institute for Medical Microbiology, Immunology and Hygiene, Medical Faculty, University of Cologne, Cologne, Germany.
Cancer Res. 2010 Mar 1;70(5):1825-34. doi: 10.1158/0008-5472.CAN-09-3175. Epub 2010 Feb 23.
Adoptive transfer of tumor-specific cytolytic T lymphocytes (CTL) results in target cell lysis by activating the intrinsic apoptotic cell death program. Not surprisingly, deregulation of the apoptotic machinery is one of the central mechanisms by which tumor cells escape immune destruction despite specific CTL recognition. Here we show that treatment with the proteasome inhibitor bortezomib sensitizes previously resistant tumor cells for cytolytic T-cell attack. Human T cells were redirected toward melanoma cells by engineered expression of an immunoreceptor with binding specificity for high molecular weight-melanoma-associated antigen. Established melanoma cell lines as well as primary melanoma cells from tumor biopsies, which are notoriously resistant toward T-cell lysis, became sensitive upon bortezomib treatment. Detailed analysis of the underlying molecular mechanism revealed that bortezomib treatment induced mitochondrial accumulation of NOXA, which potentiated the release of mitochondrial second mitochondria-derived activator of caspase (SMAC) in response to CTL effector functions, including caspase-8 and granzyme B. Our data indicate that proteasome inhibition increases the sensitivity of tumor cells toward cytolytic T-cell attack by NOXA-mediated enhancement of mitochondrial SMAC release.
过继转移肿瘤特异性细胞毒性 T 淋巴细胞（CTL）通过激活内在凋亡细胞死亡程序导致靶细胞裂解。毫不奇怪，尽管特异性 CTL 识别，凋亡机制的失调是肿瘤细胞逃避免疫破坏的核心机制之一。在这里，我们表明，蛋白酶体抑制剂硼替佐米的治疗使先前耐药的肿瘤细胞对细胞毒性 T 细胞攻击敏感。通过工程表达与高分子量-黑色素瘤相关抗原结合特异性的免疫受体，将人 T 细胞重新定向到黑色素瘤细胞。已建立的黑色素瘤细胞系以及来自肿瘤活检的原发性黑色素瘤细胞对 T 细胞溶解具有明显的耐药性，在硼替佐米治疗后变得敏感。对潜在分子机制的详细分析表明，硼替佐米治疗诱导 NOXA 的线粒体积累，这增强了线粒体第二线粒体衍生的胱天蛋白酶激活剂（SMAC）在 CTL 效应功能（包括胱天蛋白酶-8 和颗粒酶 B）下的释放。我们的数据表明，蛋白酶体抑制通过 NOXA 介导的线粒体 SMAC 释放增强增加了肿瘤细胞对细胞毒性 T 细胞攻击的敏感性。
