For decades, researchers have sought to discover tumor antigens with the goal of identifying targets that can be incorporated into therapies that induce T-cell-mediated tumor rejection; ideally, such therapies would be tailored to tumor-specific antigens of individual patients, which should diminish toxicity without affecting efficacy. Noncanonical tumor antigens and techniques to identify them could be of extreme importance: that’s why a recent review on Nature Biotechnology is focused on this issue.
These antigens originate in translation products of transcripts from non-protein-coding regions or from noncanonical transcription and/or translation processes that can be frequently dysregulated in cancers and can fuel the tumorigenic process. Altered canonical peptides are tumor specific but often patient specific, while noncanonical peptides have the potential of being both tumor specific as well as common among patients, and therefore represent attractive targets for off-the-shelf therapies. The review is therefore focused on current methods for the identification and validation of noncanonical tumor antigens, such as proteogenomics and mass-spectrometry-based immunopeptidomics: coupled with transcriptomics and ribosome profiling, this method enables the identification of thousands of noncanonical peptides, of which a substantial fraction may be detected exclusively in tumors. It’s not an easy strategy and it requires analytical validation and advanced bioinformatics solutions for the evaluation of possible antigens and their clinical implications, but authors say that these methods could uncover new clinically relevant targets. «Integration of noncanonical tumor antigen targets to current state-of-the-art immunotherapy strategies would increase the armamentarium of immunotherapy options available: efforts must therefore be made to fully explore and identify these noncanonical antigens», researchers write. «Additionally, given the accumulating number of reported noncanonical peptides, we believe that collecting these discoveries in one accessible database could enable rich insights across tumor antigen prioritization strategies, and potential stratifications and presentation of hotspots in cancer. Many attributes need to be further dissected, including the likely heterogeneity of noncanonical antigens in terms of expression in the tumor, and their immune escape mechanisms; when at last such an antigen is deemed clinically relevant and validated in preclinical models, this knowledge can be applied in different immunotherapeutic platforms, ranging from vaccination approaches, T cell therapies, T cell receptor (TCR)-mimic antibodies, bispecific TCR molecules. We think that more translational studies will uncover the full clinical implications of noncanonical antigens».