The Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Breast Cancer Are Regulated by N-Linked Glycosylation-Dependent Activation of STAT3 and STAT1

PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor activities in many cancer types. In view relatively limited efficacy checkpoint blockades against breast cancer, our recent study addressed possibility that addition its immune-inhibitory functions, promotes pro-metastatic cells themselves. Indeed, published findings demonstrated promoted functions a cell-autonomous manner, both vitro and vivo. These fully depended on integrity S283 intracellular residue PD-L1. Here, using siRNAs S283A-PD-L1 variant, we demonstrate PD-L1—tumor cell proliferation invasion, release chemokine CXCL8—required activation STAT3 STAT1 luminal A triple-negative cells. The were potently impaired upon inhibition N-linked glycosylation (kifunensine). Site-specific mutants at each sites (N35, N192, N200, N219) revealed they all required for PD-L1-induced occur; N219 site was main regulator activation, with accompanying roles N192 N200 (depending type). Using T cell-independent mouse system, found expressing N35A-PD-L1 N219A-PD-L1 had significantly lower tumorigenic metastatic than WT-PD-L1. TCGA analyses significant associations between reduced survival high levels α-mannosidase II (inferring glycosylation) patients. suggest may be used screen patients who are greater risk disease progression, modalities targeting glycosylated lead tumor progression cancer.