Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors
Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors
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DOI：
10.1073/pnas.201398198
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发表时间：
2001-09-25
影响因子：
11.1
通讯作者：
Offringa, R
中科院分区：
文献类型：
--
作者：
Medema, JP;de Jong, J;Offringa, R
实体瘤细胞免疫治疗的概念在很大程度上依赖于 I 类 MHC 限制性细胞毒性 T 淋巴细胞 (CTL) 消除肿瘤细胞的能力。然而，肿瘤常常设法逃离这些效应细胞的细胞溶解机制。因此，绘制这种逃逸发生的机制非常重要。 CTL 杀伤靶细胞涉及通过两种主要机制诱导细胞凋亡：通过死亡受体和穿孔素/颗粒酶 B (GrB) 途径。虽然肿瘤以前被证明表现出阻断死亡受体途径的机制，但我们现在证明它们还可以通过干扰穿孔素/GrB 途径来抵抗 CTL 介导的杀伤。这种逃逸机制涉及丝氨酸蛋白酶抑制剂 PI-9/SPI-6 的表达，从而使凋亡效应分子 GrB 失活。在多种人类和小鼠肿瘤中观察到 PI-9 的表达。此外，我们表明，事实上，表达导致肿瘤细胞在体外和体内对 CTL 介导的杀伤产生抵抗。我们的数据表明，PI-9/SPI-6 是决定基于 T 细胞的癌症免疫治疗方式成功与否的重要参数。
The concept for cellular immunotherapy of solid tumors relies heavily on the capacity of class I MHC-restricted cytotoxic T lymphocytes (CTLs) to eliminate tumor cells. However, tumors often have managed to escape from the cytolytic machinery of these effector cells. Therefore, it is very important to chart the mechanisms through which this escape can occur. Target-cell killing by CTLs involves the induction of apoptosis by two major mechanisms: through death receptors and the perforin/granzyme B (GrB) pathway. Whereas tumors previously were shown to exhibit mechanisms for blocking the death receptor pathway, we now demonstrate that they also can resist CTL-mediated killing through interference with the perforin/GrB pathway. This escape mechanism involves expression of the serine protease inhibitor PI-9/SPI-6, which inactivates the apoptotic effector molecule GrB. Expression of PI-9 was observed in a variety of human and murine tumors. Moreover, we show that, indeed, expression results in the resistance of tumor cells to CTL-mediated killing both in vitro and in vivo. Our data reveal that PI-9/SPI-6 is an important parameter determining the success of T cell-based immunotherapeutic modalities against cancer.