Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Drug resistance in chronic myelogenous leukemia (CML) is often associated with mutations in the BCR-ABL gene.
• Imatinib therapy can lead to relapse in CML patients due to the emergence of drug-resistant mutations.
• Understanding the immune response to these acquired mutations is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the generation of leukemia neoantigens from drug-resistant BCR-ABL mutations in imatinib-relapsed CML.
• To assess the potential of these neoantigens to be recognized by the immune system.
• To explore the possibility of neoantigen-based immunotherapy for relapsed CML.

Main Methods:

• Computational prediction of peptides derived from BCR-ABL mutations binding to MHC class I alleles.
• Assessment of peptide binding affinity to autologous HLA alleles in CML patients.
• Experimental validation of endogenous processing and presentation of a specific neoantigen (E255K mutation-derived peptide).
• Detection of antigen-specific CD8+ T cell responses.

Main Results:

• Approximately 70 peptides from 26 BCR-ABL mutations were predicted to bind common MHC class I alleles.
• Seven out of nine imatinib-resistant CML patients were predicted to generate at least one peptide binding autologous HLA alleles.
• An E255K mutation-derived peptide was confirmed to bind HLA-A3 with high affinity, and was endogenously processed and presented.
• Polyfunctional E255K-specific CD8+ T cells were detected in two patients, correlating with a clinical response to therapy.

Conclusions:

• Leukemia-driven genetic alterations in drug-resistant CML are targeted by the immune system.
• The presence of neoantigen-specific T cells is associated with a clinical response to therapy.
• Immunizing relapsed CML patients against newly acquired tumor neoantigens is a potential therapeutic strategy.