Proteasome inhibition blocks NF-κB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs.
Proteasome inhibition blocks NF-κB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs.
复制标题
DOI：
10.1158/1535-7163.mct-11-0814
复制
发表时间：
2012-06
影响因子：
5.7
通讯作者：
Economou JS
中科院分区：
文献类型：
--
作者：
Jazirehi AR;Economou JS
编码高亲和力 MART-1/HLA-A*0201 特异性 T 细胞受体 (TCR) α/β 链 (F5 CTL) 的离体工程自体淋巴细胞的过继细胞转移 (ACT) 密集浸润到转移性疾病部位，在黑色素瘤患者中介导显着但部分的临床反应。我们假设，除了异常的细胞凋亡/生存信号传导之外，MART-1 下调还可以赋予对转基因 CTL 传递的死亡信号的抵抗力。为了探索这一假设，我们在连续 F5 CTL 选择性压力下建立了来自 MART-1+/HLA-A*0201+ F5 CTL 敏感亲本 (P) 系的耐药 (R) 系的体外模型。我们最近报道了几种黑色素瘤 R 系在保留 MART-1 表达的同时，表现出 NF-κB 的组成型激活和 NF-κB 依赖性耐药因子的过度表达。另一种建立的黑色素瘤细胞系 M244 对 F5 CTL 敏感，在连续 F5 CTL 选择压力后产生 R 系，其既降低了 MART-1 表达水平，因此无法被识别，并且对 CTL 传递的凋亡信号具有抵抗力。蛋白酶体抑制剂硼替佐米阻断 NF-κB 活性，降低磷酸化 ERK1/2，增加磷酸化 JNK 水平，减少耐药因子的表达，将 MART-1 表达恢复到足够的水平，这使得 M244R 系对 F5 CTL 杀伤敏感。这些发现表明，免疫抗性肿瘤中的蛋白酶体抑制可以恢复促凋亡信号传导并改善肿瘤抗原表达。
Adoptive cell transfer (ACT) of ex vivo engineered autologous lymphocytes encoding high-affinity MART-1/HLA-A*0201-specific T-cell receptor (TCR) α/β chains (F5 CTL), densely infiltrate into sites of metastatic disease, mediating dramatic but partial clinical responses in melanoma patients. We hypothesized that MART-1 down-modulation in addition to aberrant apoptotic/survival signaling could confer resistance to death signals delivered by transgenic CTLs. To explore this hypothesis, we established an in vitro model of resistant (R) lines from MART-1+/HLA-A*0201+ F5 CTL-sensitive parental (P) lines under serial F5 CTL-selective pressure. We have recently reported that several melanoma R lines, while retaining MART-1 expression, exhibited constitutive NF-κB activation and over-expression of NF-κB-dependent resistance factors. Another established melanoma cell line M244, otherwise sensitive to F5 CTL, yielded R lines after serial F5 CTL selective pressure which had both reduced MART-1 expression levels, thus, could not be recognized, and were resistant to CTL-delivered apoptotic death signals. The proteasome inhibitor bortezomib blocked NF-κB activity, decreased phopspho-ERK1/2, increased phospho-JNK levels, reduced expression of resistance-factors, restored MART-1 expression to sufficient levels, which in combination allowed M244R lines be sensitized to F5 CTL-killing. These findings suggest that proteasome inhibition in immune resistant tumors can restore proapoptotic signaling and improve tumor antigen expression.