Nonmutant antigens highly and specifically expressed by acute myeloid leukemia cells were identified.
Major Finding: Nonmutant antigens highly and specifically expressed by acute myeloid leukemia cells were identified.
Concept: These antigens mainly arose from translation of introns and were predicted to be immunogenic.
Impact: The identified antigens, which were shared among patients, may be useful immunotherapy targets.
Vaccines based on tumor-associated antigens have not proved useful in acute myeloid leukemia (AML), and only one common mutant tumor-specific antigen (TSA)—which does not appear to be highly immunogenic—has been identified in this malignancy. However, given that MHC I is highly expressed on AML cells and that bone marrow CD8+ T cells in patients with AML show signs of antigen recognition, Ehx and colleagues investigated AML-specific aberrantly expressed nonmutant TSAs, which can arise from translation of RNAs transcribed from noncoding regions of the genome (e.g., introns). A mass spectrometry–based analysis of 19 patient-derived AML samples revealed that AMLs highly express 58 TSAs, most of which arose from translation of intronic sequences. Analysis of data from RNA-sequencing experiments on AML blasts from 437 patients revealed that many of these highly expressed TSAs were likely shared among patients, at least one of such TSAs would be expected to be presented on AML cells of the majority of patients, and disease stage—from time of diagnosis to time of relapse—did not alter the expression profile of these TSAs. Therefore, targeting the identified TSAs may be of interest in any patient with AML. Importantly, these TSAs were highly expressed not only by leukemia blasts but also by leukemia stem cells, which are thought to be the principal contributors to relapse. Supporting the hypothesis that these highly expressed TSAs are immunogenic, presentation of a greater number of these TSAs was correlated with longer survival in patients with AML. Use of a machine learning approach that predicts the probability of T-cell responsiveness to antigens provided evidence that the highly expressed TSAs were immunogenic, an idea further supported by in vitro assays and data from patient samples. Collectively, these findings demonstrate the existence of immunogenic, AML-specific antigens shared among patients and suggest that these TSAs may be useful immunotherapy targets.
Ehx G, Larouche JD, Durette C, Laverdure JP, Hesnard L, Vincent K, et al. Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes. Immunity 2021 Mar 18 [Epub ahead of print].
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