Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Acute myeloid leukemia (AML) lacks effective immunotherapies due to a scarcity of actionable immune targets.
• Current therapeutic strategies have not fully leveraged the potential of immunotherapy in AML treatment.

Purpose of the Study:

• To identify novel tumor-specific antigens (TSAs) in acute myeloid leukemia (AML) for potential immunotherapy targets.
• To investigate the origin and biogenesis of these TSAs and their correlation with immune responses and patient survival.

Main Methods:

• Proteogenomic analysis of the MHC class I-associated immunopeptidome in 19 primary AML samples.
• Identification and characterization of TSAs, including their genomic origin and association with molecular aberrations like intron retention and epigenetic changes.

Main Results:

• Identified 58 TSAs, predominantly derived from non-coding regions (86%) and lacking mutations.
• Discovered that intron retention and epigenetic alterations are key mechanisms in TSA biogenesis, with RNA expression linked to epigenetic modifier mutations.
• Observed a correlation between TSA abundance and T cell receptor clonotype expansion, cytotoxic T cell accumulation, immunoediting, and improved patient survival.

Conclusions:

• Novel, mutation-negative TSAs derived from non-coding regions are prevalent in AML.
• Intron retention and epigenetic changes drive TSA generation, offering new insights into AML immunobiology.
• These shared AML TSAs are promising targets for developing innovative immunotherapies to improve patient outcomes.