RAD21 Overexpression Causing MDSC-Induced Immunosuppression in Lung Cancer by Stimulating the CXCL13-CXCR5 Pathway

Abstract

Background: Myeloid-derived suppressor cell (MDSC)-mediated immunosuppression is an important factor involved in tumor metastasis and survival of lung cancer (LC) patients, resulting in a poor prognosis. We aimed to unravel the underlying mechanism behind this process. Methods: Bioinformatics analysis was performed to predict the expression of C-X-C motif chemokine ligand 13 (CXCL13) and to investigate the characteristic of RAD21 cohesin complex component (RAD21) in lung adenocarcinoma (LUAD). After identification of RAD21 expression and peripheral blood-derived MDSCs in LC patients, the role of RAD21 in the recruitment of LC cells to MDSCs was explored using different approaches such as cell transfection, cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA), cell co-cultivation, CXCL13 neutralization, flow cytometry, quantitative real-time reverse transcription polymerase chain reaction, and western blot. Results: It was observed that CXCL13 and RAD21 were overexpressed in LUAD or LC tissues (p < 0.001), and the RAD21 was positively linked to poor overall survival of the patients. Furthermore, LC patients had a high proportion of MDSCs in peripheral blood mononuclear cells (PBMCs) (p < 0.001). Additionally, we found that RAD21 overexpression promoted the expansion of MDSCs (p < 0.001), and enhanced the secretion of CXCL13 in LC cells, as well as C-X-C motif chemokine receptor 5 (CXCR5) in LC cell-cocultured PBMCs (p < 0.001). However, CXCL13 neutralization in LC cells reversed the effect of RAD21 overexpression on MDSC recruitment and CXCR5 secretion (p < 0.001). Conclusion: RAD21 overexpression can lead to MDSC-induced immunosuppression in LC by stimulating the CXCL13-CXCR5 pathway.