Quantitative immunopeptidomics reveals a tumor stroma-specific target for T cell therapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• T cell receptor (TCR)-based immunotherapy is a promising strategy for solid cancer treatment.
• Identifying tumor-specific antigens and high-affinity TCRs is crucial for safe and effective therapies.

Purpose of the Study:

• To discover shared tumor antigens for TCR-based adoptive T cell therapy.
• To identify high-affinity TCRs targeting these antigens for cancer treatment.

Main Methods:

• Population-scale immunopeptidomics using quantitative mass spectrometry on ~1500 tumor and normal tissue samples.
• Identification of HLA-A*02:01-restricted epitopes.
• TCR affinity enhancement and in vivo efficacy and safety studies.

Main Results:

• Identified a pan-cancer epitope from the COL6A3 gene, highly presented on tumor stroma due to alternative splicing.
• Natural COL6A3-specific TCRs showed modest activity; affinity-enhanced TCRs specifically eliminated tumors in vivo.
• Enhanced TCR variants demonstrated a favorable safety profile with no detectable off-target reactivity.

Conclusions:

• COL6A3 is a promising shared tumor antigen for TCR-based immunotherapy across multiple solid cancers.
• Affinity-enhanced COL6A3-specific TCRs offer a potential therapeutic strategy for solid tumors.
• These findings pave the way for clinical trials targeting COL6A3 in various cancers.