Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8⁺ T Cell Immunity

Area of Science:

• Cancer immunology
• Molecular oncology
• Tumor microenvironment plasticity

Background:

• Epithelial to mesenchymal transition (EMT) and its reverse (MET) alter breast cancer cell antigenicity.
• The impact of these antigenic differences on immune interactions and therapeutic exploitation remains unclear.
• Understanding EMT-driven antigen changes is crucial for developing effective immunotherapies.

Purpose of the Study:

• To investigate antigenic differences in breast cancer cells during EMT and MET.
• To identify neoantigens arising from gene expression and splicing alterations.
• To evaluate the potential of these neoantigens for enhancing anti-cancer immune responses.

Main Methods:

• Utilized a microRNA regulator to induce a more epithelial phenotype in mesenchymal-like EO771 cells.
• Employed computational analysis to identify neoantigens from somatic variants (SNVs) and alternative splicing (neojunctions).
• Administered whole cell and peptide-based vaccines to assess immune responses and cytotoxicity.

Main Results:

• Demonstrated superior cytotoxicity against the more-epithelial cells post-vaccination.
• Identified immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells.
• Found EMT-associated splicing factors conserved across mouse and human breast cancer.

Conclusions:

• EMT and MET significantly alter breast cancer cell antigenicity, creating therapeutic targets.
• Computationally identified neoantigens, particularly from neojunctions, can elicit T cell responses.
• Targeting EMT-associated antigens offers a promising strategy for improving breast cancer immunotherapy.