GALNT3 suppresses lung cancer by inhibiting myeloid-derived suppressor cell infiltration and angiogenesis in a TNFR and c-MET pathway-dependent manner

Abstract

The deregulation of polypeptide N-acetyl-galactosaminyltransferases (GALNTs) contributes to several cancers, but their roles in lung cancer remain unclear. In this study, we have identified a tumor-suppressing role of GALNT3 in lung cancer. We found that GALNT3 suppressed lung cancer development and progression in both xenograft and syngeneic mouse models. Specifically, GALNT3 suppressed lung cancer initiation by inhibiting the self-renewal of lung cancer cells. More importantly, GALNT3 attenuated lung cancer growth by preventing the creation of a favorable tumor microenvironment (TME), which was attributed to GALNT3's ability to inhibit myeloid-derived suppressor cell (MDSC) infiltration into tumor sites and subsequent angiogenesis. We also identified a GALNT3-regulated gene (GRG) signature and found that lung cancer patients whose tumors exhibit the GRG signature showed more favorable prognoses. Further investigation revealed that GALNT3 suppressed lung cancer cell self-renewal by reducing β-catenin levels, which led to reduced expression of the downstream targets of the WNT pathway. In addition, GALNT3 inhibited MDSC infiltration into tumor sites by suppressing both the TNFR1-NFκB and cMET-pAKT pathways. Specifically, GALNT3 inhibited the nuclear localization of NFκB and the c-MET-induced phosphorylation of AKT. This then led to reduced production of CXCL1, a chemokine required for MDSC recruitment. Finally, we confirmed that the GALNT3-induced inhibition of the TNFR1-NFκB and cMET-pAKT pathways involved the O-GalNAcylation of the TNFR1 and cMET receptors. In summary, we have identified GALNT3 as the first GALNT member capable of suppressing lung cancer and uncovered a novel mechanism by which GALNT3 regulates the TME.