Liu Peng, Zhao Liwei, Kroemer Guido, Kepp Oliver
Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France.
Oncoimmunology. 2019 Dec 28;9(1):1708126. doi: 10.1080/2162402X.2019.1708126. eCollection 2020.
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 and . 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.
编码钙网蛋白（CALR）的基因突变导致C末端KDEL基序缺失，使其无法保留在内质网中，并导致CALR从细胞中分泌出来。携带新型C末端的特定CALR突变体可通过血小板生成素受体的自分泌激活引发骨髓增殖性疾病。我们最近利用选择性钩留（RUSH）技术监测CALR的运输，并证明了CALR 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）对垂死癌细胞的吞噬作用。通过这种机制，突变型CALR诱导免疫抑制，降低了免疫原性抗癌化疗和PD-1阻断的疗效。
