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Secreted calreticulin mutants subvert anticancer immunosurveillance.
OncoImmunology ( IF 7.2 ) Pub Date : 2019-12-28 , DOI: 10.1080/2162402x.2019.1708126
Peng Liu 1, 2, 3, 4, 5, 6 , Liwei Zhao 1, 2, 3, 4, 5, 6 , Guido Kroemer 1, 2, 3, 4, 5, 7, 8, 9 , Oliver Kepp 1, 2, 3, 4, 5, 6
Affiliation  

Mutations of the gene coding for calreticulin (CALR) that cause the loss of the C-terminal KDEL motif abolish its retention in the endoplasmic reticulum and cause CALR to be secreted from cells. Specific CALR mutants bearing a novel C-terminus can precipitate the manifestation of myeloproliferative diseases via the autocrine activation of the thrombopoietin receptor. We recently employed the retention using selective hooks (RUSH) technology to monitor CALR trafficking and demonstrated the secretion of C-terminally truncated variants of CALR in vitro and in vivo. Of note, extracellular CALR inhibited the phagocytosis of dying cancer cells by dendritic cells (DC). Via this mechanism, mutant CALR induced immunosuppression, which decreased the efficacy of immunogenic anticancer chemotherapies and PD-1 blockade.

中文翻译:

分泌的钙网蛋白突变体破坏了抗癌免疫监测。

导致C末端KDEL基序丢失的编码钙网蛋白(CALR)的基因突变消除了其在内质网中的保留,并使CALR从细胞中分泌出来。带有一个新的C末端的特定CALR突变体可以通过血小板生成素受体的自分泌激活而促进骨髓增生性疾病的表现。我们最近采用了选择性钩子(RUSH)技术来监测CALR的转运,并在体外和体内证明了CALR的C末端截短变体的分泌。值得注意的是,细胞外CALR抑制树突状细胞(DC)对垂死的癌细胞的吞噬作用。通过这种机制,突变CALR诱导了免疫抑制,从而降低了免疫原性抗癌化学疗法和PD-1阻滞的功效。
更新日期:2019-12-28
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