Abstract
BackgroundLung 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.MethodsImmunohistochemical 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.ResultsThe 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.ConclusionOur 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.
Highlights
Lung cancer is a common malignant tumor that threatens human life and is associated with high morbidity and mortality rates
Our study demonstrates the inhibitory effect of the CALR-TLR4 complex on non-small cell lung cancer (NSCLC) progression and provides a theoretical basis for NSCLC immunotherapy
The results showed that the expression of mCALR was positively associated with the expression of DC-LAMP (Spearman r=0.251, P=0.019), which indicated a positive correlation between mCALR expression and DC infiltration in NSCLC (Figure 1C)
Summary
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. In response to the inducers of immunogenic cell death, such as doxorubicin or oxaliplatin, tumor cells release the signals of damage-associated molecular patterns (DAMPs) and promote the recruitment and activation of antigen-presenting cells, thereby stimulating anti-tumor immune responses. When tumor cells are treated with anthracyclines, the CALR-PDIA3 complex co-translocate from the endoplasmic reticulum to the cell surface, displaying an “eat me” signal and facilitating the recognition and phagocytosis of DCs. DCs present antigens and fortify the anti-tumor immune response. The mechanisms underlying the relationship between CALR and the enhanced ability of DCs remain unclear
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