IL‐8 from CD248‐expressing cancer‐associated fibroblasts generates cisplatin resistance in non‐small cell lung cancer

Abstract

AbstractChemotherapy‐resistant non‐small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer‐associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+CAFs released IL‐8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI‐H460 while decreasing the apoptotic percentage of A549 and NCI‐H460 in vitro. The CD248+CAFs‐based IL‐8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF‐κB) and elevating ATP‐binding cassette transporter B1 (ABCB1). We also revealed that the CD248+CAFs‐based IL‐8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild‐type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL‐8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF‐κB axis, which, consecutively induces the CAFs‐based secretion of IL‐8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC‐treating cisplatin.