Abstract
Intensive fundamental and clinical research in cancer immunotherapy has led to the emergence and evolution of two parallel universes with surprisingly little interactions: the realm of hematologic malignancies and that of solid tumors. Treatment of hematologic cancers using allogeneic hematopoietic cell transplantation (AHCT) serendipitously led to the discovery that T cells specific for minor histocompatibility antigens (MiHAs) could cure hematopoietic cancers. Besides, studies based on treatment of solid tumor with ex vivo-expanded tumor infiltrating lymphocytes or immune checkpoint therapy demonstrated that anti-tumor responses could be achieved by targeting tumor-specific antigens (TSAs). It is our contention that much insight can be gained by sharing the tremendous amount of data generated in the two-abovementioned universes. Our perspective article has two specific goals. First, to discuss the value of methods currently used for MiHA and TSA discovery and to explain the key role of mass spectrometry analyses in this process. Second, to demonstrate the importance of broadening the scope of TSA discovery efforts beyond classic annotated protein-coding genomic sequences.
Highlights
CLASSIFICATION OF ANTIGENIC TARGETSMHC-associated peptides (MAPs) are by-products of protein degradation by proteasomes and other proteases [1]
Four groups of MAPs can be targeted for T-cell based immunotherapy of hematologic cancers: minor histocompatibility antigens (MiHAs), tumor-associated antigens (TAAs), mutated tumor-specific antigens (TSAs), and aberrantly expressed TSAs
To the best of our knowledge, only one mutated TSAs (mTSAs) has been unambiguously validated by mass spectrometry (MS) in acute leukemias: this HLA-A∗02:01–binding peptide results from mutations in the NPM1 gene that cause the translation of a C-terminal alternative reading frame [15]
Summary
Exons represent only 2% of the genome, whereas 75% of the genome can be transcribed and potentially translated [31]. To the best of our knowledge, only one mTSA has been unambiguously validated by MS in acute leukemias: this HLA-A∗02:01–binding peptide results from mutations in the NPM1 gene that cause the translation of a C-terminal alternative reading frame [15]. Another mTSA derived from a BCR-ABL fusion protein was identified via MS analyses in 2001 [37], but was not found in a larger cohort of subjects in 2019 [38], and its immunogenicity was called into question [39].
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