Anaplastic lymphoma kinase-derived peptides presented by human leukocyte antigen (ALK-HLA complex)

Anaplastic lymphoma kinase (ALK)-derived peptides presented by human leukocyte antigen (HLA) molecules constitute a critical class of tumor-associated antigens and neoantigens in ALK-driven malignancies (1, 2). ALK is a receptor tyrosine kinase that, when mutated or fused (e.g., EML4-ALK), acts as a potent oncogene in cancers such as non-small cell lung cancer and anaplastic large cell lymphoma (5, 6). These oncogenic proteins are intracellularly processed into short peptide fragments and displayed on the cell surface by HLA class I molecules, where they can be recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes (3, 10). This peptide-HLA complex serves as a specific target for advanced immunotherapies, including therapeutic vaccines and TCR-engineered T-cell (TCR-T) therapies (5, 9). Research indicates that ALK tyrosine kinase inhibitors can enhance the presentation of these peptides by upregulating HLA expression, potentially sensitizing tumors to immune attack (3, 4). However, therapeutic challenges include the potential for immune escape through HLA downregulation and the need for precise targeting to avoid cross-reactivity with healthy tissues (14, 16). Overall, targeting the ALK-HLA complex represents a promising strategy to provide durable responses in patients who develop resistance to standard small-molecule inhibitors (6, 8).

Other names

ALK-pMHCALK-derived neoantigensALK peptide-MHC complexALK-derived CTL epitopesEML4-ALK fusion peptides

Therapeutic strategies involve the use of vaccines to prime cytotoxic T lymphocytes (CTLs) or engineered T-cell receptors (TCRs) to specifically recognize and bind the ALK peptide-HLA complex, leading to the targeted lysis of ALK-positive tumor cells. Additionally, ALK tyrosine kinase inhibitors (TKIs) can act as modulators by upregulating HLA expression and unmasking these antigens for immune recognition.