Kinase inhibition rewires the HLA-I immunopeptidome in chronic myeloid leukemia

Immunotherapy offers promising opportunities to improve immune-mediated control of chronic myeloid leukemia (CML), but its success depends on identifying antigens uniquely associated with CML. Protein kinases regulate signaling and protein turnover, influencing which peptides are presented on HLA molecules. Although earlier studies suggested that kinase inhibition can alter immune recognition of cancer cells, the underlying mechanisms remain unclear. In this study, we investigated whether targeting key kinases could reshape the CML immunopeptidome. The pharmacological inhibition of SFK, JNK, and BCR-ABL caused broad remodeling of antigen presentation, affecting the display of 4,000 HLA-I ligands. By integrating immunopeptidomics, phospho-immunopeptidomics, and proteomics, we identified three complementary mechanisms regulating antigen display. Comparing benign hematologic tissues with CML samples revealed about 90 CML-specific peptides that became more prominent after SFK or JNK inhibition. Overall, this work provides a quantitative, multi-omic framework to rationally combine kinase inhibitors with immunotherapy to boost antigen visibility and antileukemic immunity.