Immunogenic Tumor Cell Death for Optimal Anticancer Therapy: The Calreticulin Exposure Pathway
Immunogenic Tumor Cell Death for Optimal Anticancer Therapy: The Calreticulin Exposure Pathway
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DOI：
10.1158/1078-0432.ccr-09-2891
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发表时间：
2010-06-15
影响因子：
11.5
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Zitvogel, Laurence;Kepp, Oliver;Kroemer, Guido
作为对某些化疗药物（如蒽环类药物和奥沙利铂）的反应，癌细胞经历免疫原性凋亡，这意味着它们的尸体被树突状细胞吞噬，肿瘤细胞抗原被呈递给肿瘤特异性CD 8（+）T细胞，然后控制残留的肿瘤细胞。免疫原性细胞凋亡的特点之一是钙网蛋白（CRT）的早期细胞表面暴露，钙网蛋白是一种通常存在于内质网（ER）腔中的蛋白质。当由蒽环类或奥沙利铂引发时，CRT暴露途径被凋亡前ER应激和真核翻译起始因子eIF 2 α被激酶PERK磷酸化激活，随后是ER固着蛋白BAP 31的半胱天冬酶-8介导的蛋白水解，促凋亡蛋白Bax和巴克的激活，CRT从ER到高尔基体的顺行运输和含CRT囊泡的胞吐作用，最终导致CRT易位到质膜表面。中断这一复杂的途径可以消除CRT暴露，消除细胞凋亡的免疫原性，并降低抗癌化疗引起的免疫应答。我们推测，不能激活CRT暴露途径的人类癌症对免疫介导的抗癌治疗成分是难治的。临床癌症研究; 16（12）; 3100-4。（C）2010年AACR。
In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2 alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies. Clin Cancer Res; 16(12); 3100-4. (C)2010 AACR.