PD-L1 Mediated Immune Evasion in Triple Negative Breast Cancer Is Linked to the Loss of ZNF652

ABSTRACT: The intrinsic regulation of PD-L1 expression remains unclear. Here we report that ZNF652 is a potent transcription repressor of PD-L1. ZNF652 frequently loses heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription corepressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides novel insights into PD-L1 regulation, and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Chen  

PROVIDER: PXD045945 | iProX | Fri Sep 29 00:00:00 BST 2023

REPOSITORIES: iProX