Cooperation between ZEB2 and SP1 upregulates PD‑L1 and CCL2 to promote the immunosuppressive activity of tumor cells.

Abstract

Epithelial‑mesenchymal transition (EMT) is implicated in tumor progression and EMT‑inducing transcription factors play multifaceted roles; however, the molecular mechanisms underlying these processes are not well understood. Previously, we showed that ZEB2 acts cooperatively with the transcription factor SP1 to function as a transcriptional activator that promotes cancer cell invasion and survival, as well as angiogenesis. The present study reported a novel role for Zinc Finger E‑Box Binding Homeobox 2 (ZEB2) in conferring immunosuppressive activity on cancer cells, as well as the underlying molecular mechanism. ZEB2 cooperated with SP1 to upregulate transcription of CD274 and CCL2 by interacting with the proximal SP1 element in their promoters. ZEB2‑mediated programmed cell death 1 ligand 1 (PD‑L1) upregulation on tumor cells inhibited T cell activation and cytokine secretion in a co‑culture system. ZEB2 upregulated C‑C motif chemokine ligand 2 (CCL2) secretion to promote migration of macrophages and drive polarization to an M2‑like phenotype. ZEB2 suppressed the activity of tumor‑infiltrating T cells in a syngeneic mouse tumor model. Furthermore, SUMOylation of ZEB2 by PC2 was required for efficient cooperation between ZEB2 and SP1, as well as for subsequent gene expression. Clinical data showed that ZEB2 expression is associated positively with expression of CD274 and CCL2. Expression of both ZEB2 and CD274 or CBX4 has prognostic significance for predicting survival of colon cancer patients. The present study demonstrated a previously unrecognized role for ZEB2: Direct modulation of the interaction between tumor cells and immune cells. Taken together, the data increased our understanding of the molecular mechanism underlying immunosuppression mediated by an EMT‑inducing transcription factor.