Epithelial-Mesenchymal Transition is Associated with Altered Immune Composition and Cytotoxic Function in...

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Epithelial-mesenchymal transition (EMT) is crucial in breast cancer progression, metastasis, and therapy resistance.
• EMT significantly impacts the tumor immune microenvironment, influencing immune cell infiltration and function.
• The immune landscape of intermediate or partial EMT states is poorly understood.

Purpose of the Study:

• To investigate the immunological consequences of a spectrum of EMT phenotypes in breast cancer.
• To characterize the immune cell composition and function associated with different EMT states in vivo.
• To elucidate how EMT progression influences tumor immunogenicity and immune evasion.

Main Methods:

• Established five single-cell-derived clonal populations from the 4T1 mouse mammary tumor cell line representing a spectrum of EMT phenotypes.
• Analyzed tumors derived from these clones using single-cell RNA sequencing to assess EMT states and immune infiltration.
• Quantified changes in immune cell composition, gene expression (MHC, effector molecules), and functional pathways along the EMT spectrum.

Main Results:

• Tumors derived from clones retained their relative EMT states in vivo, demonstrating a graded reduction in tumor immunogenicity with EMT progression.
• EMT progression correlated with downregulation of MHC class I and II, decreased CD8+ T cell infiltration, and reduced effector gene expression (Gzmb, Ccr5, Cxcr6).
• Observed shifts in B cell composition (decreased IgG1+ plasma cells, enriched regulatory-like B cells) and functional suppression in Natural Killer (NK) cells.

Conclusions:

• EMT progression is associated with a graded alteration in immune cell recruitment and function, leading to immune suppression.
• Downregulation of MHC and effector molecules, alongside altered immune cell infiltration and function, contributes to immune resistance during EMT.
• Integrating EMT phenotyping into therapeutic strategies may help overcome immune resistance in breast cancer.