CEBPB-high dormant tumor cells drive immune evasion via S100A8 orchestrated tumor-associated macrophages reprogramming

TL;DR

This study shows that dormant tumor cells in triple-negative breast cancer resist immunotherapy by reprogramming immune cells through the CEBPB-S100A8 pathway.

Contribution

The study identifies CEBPB and S100A8 as key drivers of immune evasion in dormant tumor cells, offering a new therapeutic target for improving immunotherapy in TNBC.

Findings

Dormant tumor cells resist immunotherapy and reside in an immunosuppressive niche with M2 macrophages and low CD8+ T cell infiltration.

CEBPB maintains tumor dormancy by activating CCNG2 and orchestrating a tumor-supportive microenvironment through S100A8.

Targeting CEBPB or S100A8 can overcome immunotherapy resistance and improve tumor microenvironment in TNBC.

Abstract

Triple negative breast cancer (TNBC) poorly responds to immune checkpoint blockade (ICB) therapy. Dormant tumor cells are recognized as immunotherapy-resistant reservoirs that may lead to tumor relapse, although the underlying mechanisms remain to be fully elucidated.

Public scRNA-seq data was employed to identify dormant tumor cells in TNBC patients receiving ICB therapy. A TetOn-H2BeGFP system was used to label and track dormant tumor cells both in vivo and in vitro. CCK-8, colony formation, and PI staining assay were performed to identify CEBPB as a key factor in tumor dormancy maintenance. The role of CEBPB in immune evasion was evaluated by macrophage and CD8+ T cell proportions in tumors, via flow cytometry, immunohistochemistry, and multiplex immunofluorescence assays. RNA-seq and ChIP-seq were further employed to identify downstream targets of CEBPB, and ChIP-qPCR, qPCR, and Western blot were used to further validate these results.

We demonstrated that dormant tumor cells were resistant to ICB and resided within an immunosuppressive niche, characterized by increased M2 macrophages and reduced CD8+ T cell infiltration. CEBPB was identified as highly expressed in dormant tumor cells, where it maintained tumor dormancy by transcriptionally activating cell cycle negative regulators, particularly CCNG2. Notably, high CEBPB expression orchestrated a tumor-supportive microenvironment with macrophage recruitment, M2 macrophage polarization, and T cell suppression. Mechanistically, S100A8 was recognized as a key transcriptional target of CEBPB to promote M2 macrophage polarization. Targeting either CEBPB or S100A8 could overcome ICB resistance and remodel the tumor microenvironment.

Our study demonstrate a mechanistic link between tumor dormancy and immune evasion, highlighting the CEBPB-S100A8 axis as a promising therapeutic target to potentiate ICB efficacy in TNBC.

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