The tumor-specific antigen landscape of acute myeloid leukemia

Abstract

In theory, tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but none have been identified in acute myeloid leukemia (AML) so far. We have recently designed a proteogenomic approach allowing the identification of MHC class I-associated peptides deriving from any reading frame of all genomic regions (not only from exons). Using this approach, we could identify 82 TSAs from 18 primary human AML samples. All these TSAs derived from unmutated transcripts which were aberrantly expressed by allegedly non-coding regions of the genome (that would have been missed by conventional exome-based approaches). In agreement with previous reports showing that high intron retention is a key feature in AML, we found that introns were the main source of TSAs (54.8%). The TSAs were presented by 24 different HLA allotypes, together covering 98,04% of the world population. The examination of the expression of the RNAs coding for the TSAs showed that most of them (68%) were expressed by at least 50% of AML samples in the “The Cancer Genome Atlas” (TCGA) cohort while all of them were either expressed at very low levels or not expressed at all in normal tissues (from the “Genotype-Tissue Expression” (GTEx) project). We have yet to discover the specific epigenetic changes leading to TSA expression in cancer cells. Meanwhile, we propose that vaccination against ab- errantly expressed TSAs could be used to treat a vast majority of patients, with minimal risks of collateral damage to healthy normal tissues.,