Unveiling cross-reactivity: implications for immune response modulation in cancer

Area of Science:

• Immunology
• Computational Biology
• Structural Biology

Background:

• CD8+ T-cell receptors (TCRs) are vital for recognizing peptide-Human Leukocyte Antigen (pHLA) complexes during immune responses.
• TCRs exhibit cross-reactivity, recognizing multiple pHLA complexes, which has implications for developing immune-modulating therapies.
• Understanding TCR cross-reactivity is key for expanding T-cell clones against pathogens and tumors.

Purpose of the Study:

• To perform a comprehensive analysis of peptide-HLA (pHLA) cross-reactivity by modeling thousands of human and viral epitopes.
• To identify features of HLA-A*02:01 from spatial perspectives using docking models.
• To explore similarities between self and non-self epitopes and identify potential cross-reactive epitopes for therapeutic applications.

Main Methods:

• Modeling of 2631 unique epitopes from viral and human proteins.
• Utilizing established docking models to analyze spatial features of HLA-A*02:01.
• Analyzing CDR3 sequences from public databases for cross-reactivity patterns.
• Correlating epitope dissimilarity with T-cell activation data from published studies.

Main Results:

• Cross-reactive CDR3 sequences recognize epitopes with similar electrostatic potential, charge, and spatial location.
• A negative correlation was observed between epitope dissimilarity and T-cell activation.
• Cancer epitopes were generally more similar to self-epitopes, but distinct features differentiated viral-like cancer epitopes.
• Potential cross-reactivities between tumoral and viral epitopes were identified.

Conclusions:

• The study provides a valuable resource of thousands of pHLA complexes for T-cell cross-reactivity research.
• Identified cross-reactivities offer insights into potential therapeutic strategies for cancer and infectious diseases.
• Challenges remain in identifying cross-reactive epitopes for effective therapeutic use.