CALR-TLR4 Complex Inhibits Non-Small Cell Lung Cancer Progression by Regulating the Migration and Maturation of Dendritic Cells.
CALR-TLR4 Complex Inhibits Non-Small Cell Lung Cancer Progression by Regulating the Migration and Maturation of Dendritic Cells.
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DOI：
10.3389/fonc.2021.743050
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发表时间：
2021
影响因子：
4.7
通讯作者：
Wang K
中科院分区：
文献类型：
--
作者：
Chen R;Huang M;Yang X;Chen XH;Shi MY;Li ZF;Chen ZN;Wang K
肺癌是威胁人类生命的常见恶性肿瘤，发病率和死亡率较高。钙网蛋白（CALR）是非小细胞肺癌（NSCLC）免疫原性细胞死亡的特征性抗原，与抗肿瘤免疫密切相关，但其抗肿瘤免疫的具体机制尚不清楚。免疫组化染色检测NSCLC组织中CALR和树突状细胞溶酶体相关膜糖蛋白（DC-LAMP）的表达。细胞上清液用于诱导树突状细胞（DC）的迁移和成熟。采用Western blot和实时PCR研究CALR-Toll样受体4（TLR4）-MyD88信号通路中相应分子的表达。进行体内实验来评估 mCALR 在肺癌进展中的作用。 NSCLC细胞膜上CALR的表达（mCALR）与NSCLC中DC浸润呈正相关，与NSCLC患者的预后密切相关。此外，mCALR通过激活CALR-TLR4-MyD88信号传导并增加TNFα和CCL19的分泌来促进DC的迁移和成熟，而TNFα和CCL19的分泌因TLR4的缺失而受到抑制。体内实验表明，mCALR 通过促进肺癌组织中的 DC 浸润来抑制肺癌进展。我们的研究探讨了CALR-TLR4复合物在DC迁移和成熟中的功能和机制，并研究了CALR-TLR4复合物对肺癌进展的抑制作用，为NSCLC的免疫治疗提供了理论基础和思路。
Lung cancer is a common malignant tumor that threatens human life and is associated with high morbidity and mortality rates. Calreticulin (CALR) is a antigen characteristic of immunogenic cell death in non-small cell lung cancer (NSCLC), which is closely related to anti-tumor immunity, but its specific mechanism in anti-tumor immunity remains unclear. Immunohistochemical staining was performed to detect the expression of CALR and dendritic cell-lysosome-associated membrane glycoprotein (DC-LAMP) in NSCLC tissues. The cell supernatant was used to induce migration and maturation of dendritic cells (DCs). Western blot and real-time PCR were used to investigate the corresponding molecule expression in the CALR-Toll-like receptor 4 (TLR4)-MyD88 signaling pathway. In vivo experiments were conducted to evaluate the role of mCALR in lung cancer progression. The expression of CALR on NSCLC cell membrane (mCALR) and DC infiltration in NSCLC were positively correlated and were closely related to the prognosis of NSCLC patients. Moreover, mCALR facilitated the migration and maturation of DCs by activating CALR-TLR4-MyD88 signaling and increasing the secretion of TNFα and CCL19, which was inhibited by the loss of TLR4. In vivo experiments demonstrated that mCALR inhibited lung cancer progression by facilitating DC infiltration in lung cancer tissues. Our study explores the function and mechanism of the CALR-TLR4 complex in DC migration and maturation and investigates the inhibitory effect of the CALR-TLR4 complex on lung cancer progression, providing a theoretical basis and ideas for immunotherapy of NSCLC.
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