Multiscale Modeling Uncovers Macrophage Infiltration and TNF-α Signaling Networks for Targeting in Inflammatory...

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Inflammatory breast cancer (IBC) has dismal survival rates and high metastatic potential.
• Tumor emboli, diffuse cell clusters in dermal tissue and lymphatics, characterize IBC and are linked to poor prognosis.
• The molecular mechanisms driving the IBC tumor emboli phenotype and its interaction with the immune microenvironment are poorly understood.

Purpose of the Study:

• To investigate the interaction between tumor emboli and the tumor immune microenvironment (TiME) in IBC.
• To identify molecular targets within the tumor emboli microenvironment for therapeutic intervention.

Main Methods:

• Spatial immunophenotyping of clinical IBC samples.
• Ex vivo culture of patient-derived IBC cell lines in a lymphatic-like platform.
• Transcriptomic and proteomic analysis of tumor emboli.
• Intravital imaging using a transgenic murine model (CX3cr1GFP).
• In vivo targeting of TNFα-signaling with Birinapant.

Main Results:

• Tumor emboli cultures showed upregulated TNFR signaling, CXCL8, and immune cell chemotaxis genes compared to 2D cultures.
• IBC patient tumors exhibited high levels of CD163+ tumor-associated macrophages (TAMs).
• Macrophage migration towards tumor cell clusters was confirmed in vivo.
• Birinapant treatment inhibited the tumor emboli phenotype in the murine model.

Conclusions:

• This study identifies TNFα signaling and macrophage infiltration as key components of IBC tumor emboli.
• Targeting TNFα signaling offers a potential therapeutic strategy to induce cell death and reduce macrophage influence in IBC.
• These findings provide a basis for developing novel treatments to improve IBC patient outcomes.