Neddylation pathway promotes myeloid-derived suppressor cell infiltration via NF-?B-mCXCL5 signaling in lung cancer

Myeloid-derived suppressor cells (MDSCs), a population derived from immature myeloid progenitors, are present in the tumors of patients and highly protumorigenic. However, the molecular mechanisms regulating MDSC infiltration remain unclear. Neddylation pathway is overactivated in multiple cancers and has a significant role in tumor progression. We established a subcutaneous transplantation model of Lewis lung cancer in mice and showed that inactivation of neddylation pathway inhibits MDSC infiltration and impairs lung cancer growth. A high expression level of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is positively correlated with MDSC infiltration in human lung adenocarcinomas (LUADs). Moreover, inactivation of neddylation pathway inhibits the expression of murine CXCL5 (mCXCL5; human homolog CXCL6, hCXCL6), an important cytokine implicated in MDSC recruitment. Mechanistically, inactivation of neddylation pathway in-hibits activity of Cullin-RING ligase 1, a typical neddylation substrate, and induces accumulation of phosphor-ylated I kappa B alpha and subsequent blockage of NF-kappa B translocation, thus suppressing transcriptional activation of mCxcl5 or hCXCL6. Collectively, our data suggest that neddylation-NF-kappa B-mCXCL5 axis is involved in MDSC recruitment to the tumor sites and demonstrate that neddylation pathway is a good therapeutic target for pa-tients with LUAD, particularly those receiving anti-MDSC therapy.

Automated summary

The neddylation pathway has been shown to play a significant role in regulating MDSC infiltration in lung adenocarcinomas (LUADs). Inhibition of this pathway can suppress the infiltration of MDSCs and impede lung cancer growth by inhibiting the expression of mCXCL5. The neddylation-NF-κB-mCXCL5 axis is involved in the recruitment of MDSCs to tumor sites, highlighting the neddylation pathway as a potential therapeutic target for LUAD patients, especially those undergoing anti-MDSC therapy.