The CHST11‐CP‐metal ionic axis contributes to NSCLC immune escape and metastasis

Abstract

Escaping of immune surveillance is essential for tumor metastasis. Recently, intratumoral metal ionic balance plays an important role in controlling cancer immune checkpoint protein expression and tumor immune escape. Copper (Cu) promotes the expression of PD‐L1. In contrast to Cu, heme biosynthesis disturbs PD‐L1 expression. Heme protein is a kind of metalloproteins with ferrous iron (Fe2+)‐porphyrin core. Here, we found CHST11 served as a pro‐metastatic gene in non‐small cell lung cancer (NSCLC). We further identified the expression of ceruloplasmin (CP) was regulated by CHST11. CP is not only the major blood Cu carrier protein but also a Cu‐dependent ferroxidase in iron metabolism. It may hint a crosstalk mechanism between lung cancer metastasis and tumor immune surveillance through the CHST11‐CP axis. CP was also associated with poor prognosis in patients with NSCLC. Both ectopic CP expression and high intracellular ionic stimulations, like ferric iron and copper, promoted NSCLC progression, such as in vitro migration and invasion, as well as in vivo tumorigenesis abilities in Nod‐SCID mice. The ionic chelator treatments repressed in vitro metastatic potential and, interestingly, regulated the gene expressions of immune checkpoints in NSCLC cells. By using microarray analysis, we found CHST11 controlled CP expression through interferon‐gamma (IFNγ), Janus kinase (JAK), and signal transducer and activator of transcription (STAT) pathways. Treatment with ruxolitinib, a JAK inhibitor, suppressed the expressions of CP and immune checkpoint proteins. In conclusion, our findings prove that the CHST11‐CP axis plays an important role in both NSCLC immune escape and metastasis through IFNγ‐JAK‐STAT pathway. The combination of an iron chelator and ruxolitinib may provide a potential translation application that protects patients with NSCLC from cancer immune escape and metastasis.